Re: [ccp4bb] challenges in structural biology

[Andrew Arvai]

Since you want to think big, I would suggest as a challenge to solve
the 3-D atomic structure of a human chromosome. Not the proteins
encoded by the DNA, but the 3-D structure of an entire chromosome.
Only about 1 percent of DNA codes for proteins. To understand gene
regulation and what makes a human different from a mouse, understanding
the 3-D organization of an entire chromosome will be necessary.

The first protein structure in 1958 (myoglobin) had about 1200 atoms.
Now, about 60 years later we have the structure of the 70S ribosome (6ND5)
with about 30 atoms - about 250 times larger than myoglobin.
Chromosomes are quite a bit larger, with about 8 billion atoms
each - over 26000 times larger than the 70S ribosome. This won't be
solved with X-ray crystallography, but perhaps with a trillion dollar
cryo-em microscope / detector combined with other technologies it
might.



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Re: [ccp4bb] AW: [EXTERNAL] Re: [ccp4bb] AW: [ccp4bb] challenges in structural biology

[Michael Hothorn]

Dear Patrick, plants do have a rather complex immune system. best regards, 
Michael

On September 21, 2019 10:18:39 AM GMT+02:00, Patrick Shaw Stewart 
 wrote:
>Dear Herman
>
>Animals that are sick tend not to move around a lot.  One can imagine
>that
>this limits the tendency for animal viruses and other animal pathogens
>to
>become more and more virulent, because the very virulent strains won't
>spread as fast.  And (importantly) when the most virulent strains
>finally
>arrive at some particular location, they will find that their potential
>hosts are already immune*.
>
>Since plants don't move around, I have always wondered why plant
>pathogens
>don't increase in virulence until they wipe out their hosts, especially
>when you bear in mind that plants don't have complex immune systems.
>
>Could these multiple genes be a way to avoid being wiped out by
>disease?
>Ie if the plant gets sick, it just switches on a batch of "reserve"
>genes**.  Is that possible?
>
>Thx, Patrick
>
>
>* This is a pet theory of mine: https://oldwivesandvirologists.blog
>
>**Or maybe the expression of these genes is random - two genetically
>identical individuals growing side-by-side might express different
>batches
>of genes on a random basis.  Again, this might be mainly about disease
>prevention.
>
>
>
>On Fri, Sep 20, 2019 at 8:51 AM  wrote:
>
>> Dear John,
>>
>> Plants cannot walk away to a more favorable spot. They remain stuck
>where
>> they germinate, e.g. whether the place is sunny, shady, wet, dry,
>fertile,
>> poor etc. So plants compensate by having a lot of genes available to
>be
>> able to adapt to the particular spot where happen to be. And indeed,
>plants
>> have usually more genes then animals!
>>
>> Best,
>>
>> Herman
>>
>>
>>
>> *Von:* CCP4 bulletin board [mailto:CCP4BB@JISCMAIL.AC.UK] *Im Auftrag
>von
>> *John R Helliwell
>> *Gesendet:* Freitag, 20. September 2019 09:19
>> *An:* CCP4BB@JISCMAIL.AC.UK
>> *Betreff:* [EXTERNAL] Re: [ccp4bb] AW: [ccp4bb] challenges in
>structural
>> biology
>>
>>
>>
>> *EXTERNAL : *Real sender is owner-ccp...@jiscmail.ac.uk
>>
>>
>>
>> Dear Martin,
>>
>> Many thanks for these details of the size of the human genome over
>the
>> decades and also the news of your most interesting upcoming review. I
>shall
>> read it with great interest.
>>
>> Incidentally is the over 4 genes for the rice genome number
>correct?
>> This number caught my eye as being interesting how the rice genome is
>more
>> complicated than our genome.
>>
>> Best wishes,
>>
>> John
>>
>> Emeritus Professor John R Helliwell DSc
>>
>>
>>
>>
>>
>>
>>
>>
>> On 19 Sep 2019, at 08:35, Kollmar, Martin 
>wrote:
>>
>> Dear John,
>>
>> the „100,000 human genes“ is a long-standing myth broad forward by
>the
>> initiators of the U.S. human genome sequencing projects in 1990. This
>large
>> number completely contradicted all genetics and mutation data since
>the 1940
>> th, but the sequencing community (genome, cDNA, EST) didn’t read even
>the
>> standard text books. Thus, the “30,000” genes published with the two
>human
>> genome papers in 2001 are not “surprisingly low” but just in
>accordance
>> with the predictions and the data since the 1940th. The gene number
>went
>> down to about 23,000 already in 2004, and the current numbers
>(depending on
>> database) range around 20,000 human protein-coding genes. The myth of
>the
>> large numbers is only propagated by those who profit from larger
>numbers
>> (e.g. bigger grants, papers in higher IF journals, big consortia).
>>
>>
>>
>> I have written a review about the current state (and history) of the
>human
>> protein-coding genes, which will appear online in BioEssays soon and
>> finally in the November issue (will be open access). In this review
>there
>> will be some (hopefully) useful plots showing the gene numbers since
>the
>> 1940th and a detailed review of all the numbers and their
>experimental
>> basis (most were actually just extrapolations from small-scale data).
>>
>>
>>
>> Please excuse this kind of self-advertisement, but it is really more
>than
>> time to move this myth out of science literature and communication.
>>
>>
>>
>> Best regards,
>>
>> Martin
>>
>>
>>
>> Priv. Doz. Dr. Martin Kollmar
>>
>>
>>
>> Group S

Re: [ccp4bb] AW: [EXTERNAL] Re: [ccp4bb] AW: [ccp4bb] challenges in structural biology

[Patrick Shaw Stewart]

Dear Herman

Animals that are sick tend not to move around a lot.  One can imagine that
this limits the tendency for animal viruses and other animal pathogens to
become more and more virulent, because the very virulent strains won't
spread as fast.  And (importantly) when the most virulent strains finally
arrive at some particular location, they will find that their potential
hosts are already immune*.

Since plants don't move around, I have always wondered why plant pathogens
don't increase in virulence until they wipe out their hosts, especially
when you bear in mind that plants don't have complex immune systems.

Could these multiple genes be a way to avoid being wiped out by disease?
Ie if the plant gets sick, it just switches on a batch of "reserve"
genes**.  Is that possible?

Thx, Patrick


* This is a pet theory of mine: https://oldwivesandvirologists.blog

**Or maybe the expression of these genes is random - two genetically
identical individuals growing side-by-side might express different batches
of genes on a random basis.  Again, this might be mainly about disease
prevention.



On Fri, Sep 20, 2019 at 8:51 AM  wrote:

> Dear John,
>
> Plants cannot walk away to a more favorable spot. They remain stuck where
> they germinate, e.g. whether the place is sunny, shady, wet, dry, fertile,
> poor etc. So plants compensate by having a lot of genes available to be
> able to adapt to the particular spot where happen to be. And indeed, plants
> have usually more genes then animals!
>
> Best,
>
> Herman
>
>
>
> *Von:* CCP4 bulletin board [mailto:CCP4BB@JISCMAIL.AC.UK] *Im Auftrag von
> *John R Helliwell
> *Gesendet:* Freitag, 20. September 2019 09:19
> *An:* CCP4BB@JISCMAIL.AC.UK
> *Betreff:* [EXTERNAL] Re: [ccp4bb] AW: [ccp4bb] challenges in structural
> biology
>
>
>
> *EXTERNAL : *Real sender is owner-ccp...@jiscmail.ac.uk
>
>
>
> Dear Martin,
>
> Many thanks for these details of the size of the human genome over the
> decades and also the news of your most interesting upcoming review. I shall
> read it with great interest.
>
> Incidentally is the over 4 genes for the rice genome number correct?
> This number caught my eye as being interesting how the rice genome is more
> complicated than our genome.
>
> Best wishes,
>
> John
>
> Emeritus Professor John R Helliwell DSc
>
>
>
>
>
>
>
>
> On 19 Sep 2019, at 08:35, Kollmar, Martin  wrote:
>
> Dear John,
>
> the „100,000 human genes“ is a long-standing myth broad forward by the
> initiators of the U.S. human genome sequencing projects in 1990. This large
> number completely contradicted all genetics and mutation data since the 1940
> th, but the sequencing community (genome, cDNA, EST) didn’t read even the
> standard text books. Thus, the “30,000” genes published with the two human
> genome papers in 2001 are not “surprisingly low” but just in accordance
> with the predictions and the data since the 1940th. The gene number went
> down to about 23,000 already in 2004, and the current numbers (depending on
> database) range around 20,000 human protein-coding genes. The myth of the
> large numbers is only propagated by those who profit from larger numbers
> (e.g. bigger grants, papers in higher IF journals, big consortia).
>
>
>
> I have written a review about the current state (and history) of the human
> protein-coding genes, which will appear online in BioEssays soon and
> finally in the November issue (will be open access). In this review there
> will be some (hopefully) useful plots showing the gene numbers since the
> 1940th and a detailed review of all the numbers and their experimental
> basis (most were actually just extrapolations from small-scale data).
>
>
>
> Please excuse this kind of self-advertisement, but it is really more than
> time to move this myth out of science literature and communication.
>
>
>
> Best regards,
>
> Martin
>
>
>
> Priv. Doz. Dr. Martin Kollmar
>
>
>
> Group Systems Biology of Motor Proteins
>
> Department NMR-based Structural Biology
>
> Max-Planck-Institute for Biophysical Chemistry
>
> Am Fassberg 11
>
> 37077 Goettingen
>
> Deutschland
>
>
>
> www.motorprotein.de
> <https://urldefense.proofpoint.com/v2/url?u=http-3A__www.motorprotein.de_=DwMFaQ=Dbf9zoswcQ-CRvvI7VX5j3HvibIuT3ZiarcKl5qtMPo=HK-CY_tL8CLLA93vdywyu3qI70R4H8oHzZyRHMQu1AQ=32JRE8HZHPdJxpaoz1sLz-PnTi-D_zZTMfdQs_FdEcI=IWuNyBzheAGJ761iddc78L4lz7sB21cKQTrawbV4j0M=>
> (Homepage)
>
> www.cymobase.org
> <https://urldefense.proofpoint.com/v2/url?u=http-3A__www.cymobase.org_=DwMFaQ=Dbf9zoswcQ-CRvvI7VX5j3HvibIuT3ZiarcKl5qtMPo=HK-CY_tL8CLLA93vdywyu3qI70R4H8oHzZyRHMQu1AQ=32JRE8HZHPdJxpaoz1sLz-P

[ccp4bb] AW: [EXTERNAL] Re: [ccp4bb] AW: [ccp4bb] challenges in structural biology

[Herman . Schreuder]

Dear John,
Plants cannot walk away to a more favorable spot. They remain stuck where they 
germinate, e.g. whether the place is sunny, shady, wet, dry, fertile, poor etc. 
So plants compensate by having a lot of genes available to be able to adapt to 
the particular spot where happen to be. And indeed, plants have usually more 
genes then animals!
Best,
Herman

Von: CCP4 bulletin board [mailto:CCP4BB@JISCMAIL.AC.UK] Im Auftrag von John R 
Helliwell
Gesendet: Freitag, 20. September 2019 09:19
An: CCP4BB@JISCMAIL.AC.UK
Betreff: [EXTERNAL] Re: [ccp4bb] AW: [ccp4bb] challenges in structural biology


EXTERNAL : Real sender is owner-ccp...@jiscmail.ac.uk

Dear Martin,
Many thanks for these details of the size of the human genome over the decades 
and also the news of your most interesting upcoming review. I shall read it 
with great interest.
Incidentally is the over 4 genes for the rice genome number correct? This 
number caught my eye as being interesting how the rice genome is more 
complicated than our genome.
Best wishes,
John
Emeritus Professor John R Helliwell DSc




On 19 Sep 2019, at 08:35, Kollmar, Martin 
mailto:m...@nmr.mpibpc.mpg.de>> wrote:
Dear John,
the „100,000 human genes“ is a long-standing myth broad forward by the 
initiators of the U.S. human genome sequencing projects in 1990. This large 
number completely contradicted all genetics and mutation data since the 1940th, 
but the sequencing community (genome, cDNA, EST) didn’t read even the standard 
text books. Thus, the “30,000” genes published with the two human genome papers 
in 2001 are not “surprisingly low” but just in accordance with the predictions 
and the data since the 1940th. The gene number went down to about 23,000 
already in 2004, and the current numbers (depending on database) range around 
20,000 human protein-coding genes. The myth of the large numbers is only 
propagated by those who profit from larger numbers (e.g. bigger grants, papers 
in higher IF journals, big consortia).

I have written a review about the current state (and history) of the human 
protein-coding genes, which will appear online in BioEssays soon and finally in 
the November issue (will be open access). In this review there will be some 
(hopefully) useful plots showing the gene numbers since the 1940th and a 
detailed review of all the numbers and their experimental basis (most were 
actually just extrapolations from small-scale data).

Please excuse this kind of self-advertisement, but it is really more than time 
to move this myth out of science literature and communication.

Best regards,
Martin

Priv. Doz. Dr. Martin Kollmar

Group Systems Biology of Motor Proteins
Department NMR-based Structural Biology
Max-Planck-Institute for Biophysical Chemistry
Am Fassberg 11
37077 Goettingen
Deutschland

www.motorprotein.de<https://urldefense.proofpoint.com/v2/url?u=http-3A__www.motorprotein.de_=DwMFaQ=Dbf9zoswcQ-CRvvI7VX5j3HvibIuT3ZiarcKl5qtMPo=HK-CY_tL8CLLA93vdywyu3qI70R4H8oHzZyRHMQu1AQ=32JRE8HZHPdJxpaoz1sLz-PnTi-D_zZTMfdQs_FdEcI=IWuNyBzheAGJ761iddc78L4lz7sB21cKQTrawbV4j0M=>
 (Homepage)
www.cymobase.org<https://urldefense.proofpoint.com/v2/url?u=http-3A__www.cymobase.org_=DwMFaQ=Dbf9zoswcQ-CRvvI7VX5j3HvibIuT3ZiarcKl5qtMPo=HK-CY_tL8CLLA93vdywyu3qI70R4H8oHzZyRHMQu1AQ=32JRE8HZHPdJxpaoz1sLz-PnTi-D_zZTMfdQs_FdEcI=fMYqMfsorSLNspHq5-Wx_WDkChCYsDr9NEXwrGsKvpo=>
 (Database of Cytoskeletal and Motor Proteins)
www.diark.org<https://urldefense.proofpoint.com/v2/url?u=http-3A__www.diark.org_=DwMFaQ=Dbf9zoswcQ-CRvvI7VX5j3HvibIuT3ZiarcKl5qtMPo=HK-CY_tL8CLLA93vdywyu3qI70R4H8oHzZyRHMQu1AQ=32JRE8HZHPdJxpaoz1sLz-PnTi-D_zZTMfdQs_FdEcI=QB0-HJUz9wLSC-Xd5_Bj6Gnhx70AaYoxkD8kIu7Ub6A=>
 (diArk - a resource for eukaryotic genome research)
www.webscipio.org<https://urldefense.proofpoint.com/v2/url?u=http-3A__www.webscipio.org_=DwMFaQ=Dbf9zoswcQ-CRvvI7VX5j3HvibIuT3ZiarcKl5qtMPo=HK-CY_tL8CLLA93vdywyu3qI70R4H8oHzZyRHMQu1AQ=32JRE8HZHPdJxpaoz1sLz-PnTi-D_zZTMfdQs_FdEcI=sy5FDRUX22Q-6XcBo-X_-tgZenKZRLf9N__I8x3pnBo=>
 (Scipio - eukaryotic gene identification)

Von: CCP4 bulletin board mailto:CCP4BB@JISCMAIL.AC.UK>> 
Im Auftrag von John R Helliwell
Gesendet: Donnerstag, 19. September 2019 08:51
An: CCP4BB@JISCMAIL.AC.UK<mailto:CCP4BB@JISCMAIL.AC.UK>
Betreff: Re: [ccp4bb] challenges in structural biology

Dear James,
Well, 100,000 genes used to be the estimate of the size of the human genome.
(eg see 
https://physicsworld.com/a/protein-crystallography-the-human-genome-in-3-d/<https://urldefense.proofpoint.com/v2/url?u=https-3A__physicsworld.com_a_protein-2Dcrystallography-2Dthe-2Dhuman-2Dgenome-2Din-2D3-2Dd_=DwMFaQ=Dbf9zoswcQ-CRvvI7VX5j3HvibIuT3ZiarcKl5qtMPo=HK-CY_tL8CLLA93vdywyu3qI70R4H8oHzZyRHMQu1AQ=32JRE8HZHPdJxpaoz1sLz-PnTi-D_zZTMfdQs_FdEcI=Au_C7wioq-2-qa1kL026q6V6n88YzwYRsi2fGz6xjpg=>
 )
It seems it has got easier, albeit still gargantuan, at ~30,000 genes to be 
expressed into proteins.

Meanwhile funding agencies also look out

Re: [ccp4bb] AW: [ccp4bb] challenges in structural biology

[John R Helliwell]

Dear Martin,
Many thanks for these details of the size of the human genome over the decades 
and also the news of your most interesting upcoming review. I shall read it 
with great interest.
Incidentally is the over 4 genes for the rice genome number correct? This 
number caught my eye as being interesting how the rice genome is more 
complicated than our genome.
Best wishes,
John 
Emeritus Professor John R Helliwell DSc




> On 19 Sep 2019, at 08:35, Kollmar, Martin  wrote:
> 
> Dear John,
> the „100,000 human genes“ is a long-standing myth broad forward by the 
> initiators of the U.S. human genome sequencing projects in 1990. This large 
> number completely contradicted all genetics and mutation data since the 
> 1940th, but the sequencing community (genome, cDNA, EST) didn’t read even the 
> standard text books. Thus, the “30,000” genes published with the two human 
> genome papers in 2001 are not “surprisingly low” but just in accordance with 
> the predictions and the data since the 1940th. The gene number went down to 
> about 23,000 already in 2004, and the current numbers (depending on database) 
> range around 20,000 human protein-coding genes. The myth of the large numbers 
> is only propagated by those who profit from larger numbers (e.g. bigger 
> grants, papers in higher IF journals, big consortia).
>  
> I have written a review about the current state (and history) of the human 
> protein-coding genes, which will appear online in BioEssays soon and finally 
> in the November issue (will be open access). In this review there will be 
> some (hopefully) useful plots showing the gene numbers since the 1940th and a 
> detailed review of all the numbers and their experimental basis (most were 
> actually just extrapolations from small-scale data).
>  
> Please excuse this kind of self-advertisement, but it is really more than 
> time to move this myth out of science literature and communication.
>  
> Best regards,
> Martin
>  
> Priv. Doz. Dr. Martin Kollmar
>  
> Group Systems Biology of Motor Proteins
> Department NMR-based Structural Biology
> Max-Planck-Institute for Biophysical Chemistry
> Am Fassberg 11
> 37077 Goettingen
> Deutschland
>  
> www.motorprotein.de (Homepage)
> www.cymobase.org (Database of Cytoskeletal and Motor Proteins)
> www.diark.org (diArk - a resource for eukaryotic genome research)
> www.webscipio.org (Scipio - eukaryotic gene identification)
>  
> Von: CCP4 bulletin board  Im Auftrag von John R 
> Helliwell
> Gesendet: Donnerstag, 19. September 2019 08:51
> An: CCP4BB@JISCMAIL.AC.UK
> Betreff: Re: [ccp4bb] challenges in structural biology
>  
> Dear James,
> Well, 100,000 genes used to be the estimate of the size of the human genome.
> (eg see 
> https://physicsworld.com/a/protein-crystallography-the-human-genome-in-3-d/ )
> It seems it has got easier, albeit still gargantuan, at ~30,000 genes to be 
> expressed into proteins.
>  
> Meanwhile funding agencies also look out for Big Ideas:-
> https://epsrc.ukri.org/research/ourportfolio/epsrcbigideas/?utm_source=Twitter_medium=social_campaign=SocialSignIn
> and even helpfully spell out the difference between a Big Idea and a Grand 
> Challenge!
> Maybe an “Open Door for funding” for us all?
>  
> Today also the repertoire of methods capable of resolving in 3D protein 
> structures has expanded further with the splendid development of cryoEM. 
>  
> To define challenges in terms of projects, as Max Perutz taught us 
> (“Haemoglobin the Molecular Lung”) avoids methods looking for problems.
>  
> Also a final thought, how we organise ourselves in different areas of the 
> World varies according to our cultural traditions. So the Big Project is 
> neutral to politics and can accommodate all contributions however so arrived 
> at.
>  
> “What shall we do with it?”
> As Darwin taught us, first make your Collection..
>  
> Greetings!
> John 
>  
> 
> Emeritus Professor John R Helliwell DSc
> https://www.crcpress.com/The-Whats-of-a-Scientific-Life/Helliwell/p/book/9780367233020
>  
>  
> 
> On 18 Sep 2019, at 22:15, James Holton  wrote:
> 
> Thank you John, an excellent choice as always.  Here is your trillion 
> dollars!  Now, what are you going to do with it?
> 
> Do you think simply scaling up current technology could reach this goal?  
> More screens, more combinations, more compute cycles?  Remember, if you want 
> the "genome/proteome" you need all of it, including all those super-cool 
> human membrane proteins we gave up on because they were too hard.  
> 
> I think we all have at least one of those projects in our past.  What was the 
> show-stopper in the end?  Did they just not grow crystals? Poor diffraction? 
&g

Re: [ccp4bb] challenges in structural biology

[Phoebe A. Rice]

Giving the vagaries of alternate splicing, is there one discrete number of 
human genes out there to be determined?
And what percentage of the encoded mass of protein is actually structured?

Another more biochemical challenge for structural biology is figuring out how 
to deal with weak cooperative interactions among multiple flexible partners.

~~~
Phoebe A. Rice
Dept. of Biochem & Mol. Biol. and
  Committee on Microbiology
https://voices.uchicago.edu/phoebericelab/


From: CCP4 bulletin board  on behalf of John R Helliwell 

Reply-To: John R Helliwell 
Date: Thursday, September 19, 2019 at 1:51 AM
To: "CCP4BB@JISCMAIL.AC.UK" 
Subject: Re: [ccp4bb] challenges in structural biology

Dear James,
Well, 100,000 genes used to be the estimate of the size of the human genome.
(eg see 
https://physicsworld.com/a/protein-crystallography-the-human-genome-in-3-d/ )
It seems it has got easier, albeit still gargantuan, at ~30,000 genes to be 
expressed into proteins.

Meanwhile funding agencies also look out for Big Ideas:-
https://epsrc.ukri.org/research/ourportfolio/epsrcbigideas/?utm_source=Twitter_medium=social_campaign=SocialSignIn
and even helpfully spell out the difference between a Big Idea and a Grand 
Challenge!
Maybe an “Open Door for funding” for us all?

Today also the repertoire of methods capable of resolving in 3D protein 
structures has expanded further with the splendid development of cryoEM.

To define challenges in terms of projects, as Max Perutz taught us 
(“Haemoglobin the Molecular Lung”) avoids methods looking for problems.

Also a final thought, how we organise ourselves in different areas of the World 
varies according to our cultural traditions. So the Big Project is neutral to 
politics and can accommodate all contributions however so arrived at.

“What shall we do with it?”
As Darwin taught us, first make your Collection..

Greetings!
John

Emeritus Professor John R Helliwell DSc
https://www.crcpress.com/The-Whats-of-a-Scientific-Life/Helliwell/p/book/9780367233020



On 18 Sep 2019, at 22:15, James Holton 
mailto:jmhol...@lbl.gov>> wrote:
Thank you John, an excellent choice as always.  Here is your trillion dollars!  
Now, what are you going to do with it?

Do you think simply scaling up current technology could reach this goal?  More 
screens, more combinations, more compute cycles?  Remember, if you want the 
"genome/proteome" you need all of it, including all those super-cool human 
membrane proteins we gave up on because they were too hard.

I think we all have at least one of those projects in our past.  What was the 
show-stopper in the end?  Did they just not grow crystals? Poor diffraction? 
Weird diffraction? Twinned? Won't phase? Won't refine to a decent R factor? 
Annoying reviewer? Did you try cryoEM? NMR? and did they not work either?

I think a key question for all of us is: what new capability would make you 
decide to go back and pick up your old favorite project again?  Without your 
structure, the genome is incomplete.

-James Holton
MAD Scientist
On 9/16/2019 12:24 AM, John R Helliwell wrote:
Dear James,
Here you go, a “grand challenge” suggestion to consider for funding from the 
“James Holton Foundation for structural biology research”:-
“The human genome/proteome in 3-D”
Greetings,
John
Emeritus Professor John R Helliwell DSc




On 14 Sep 2019, at 02:39, James Holton 
mailto:jmhol...@lbl.gov>> wrote:

I would like to thank everyone who took the time to respond to my question that 
started this thread.  It is really good for me to get a sense of the community 
perspective.  Some debates were predictable, others not.  Many ideas I agree 
with, some not so much.  All were thought-provoking. I think this is going to 
be a really good GRC!

Something I did not expect to distill from all the responses is that the 
dominant challenge in structural biology is financial. The most common strategy 
suggested for addressing this challenge was torpedoing other scientists in 
similar fields, perhaps expecting to benefit from the flotsam.  Historically, 
this strategy is often counterproductive and at best inefficient. The good news 
is there is a lot of room for improvement. In reality, we are all on the same 
ship, and the people in our funding agencies fighting to get us what we need 
can be much more effective when armed with positive ideas and clear plans.  
That is a better strategy for overcoming this challenge.

To this end, my first GRC session title is going to be:

"If I had a trillion dollars for structural biology"

I think we can all agree that science in general is vastly under-funded 
relative to the impact it has on the human condition.  For example, I estimate 
the value of a general cure for cancer to be at least a trillion dollars.  This 
is based on the lives claimed every year, multiplied by how much one person 
would gladly pay after being diagnosed (amortized over the res

[ccp4bb] AW: [ccp4bb] challenges in structural biology

[Kollmar, Martin]

Dear John,
the „100,000 human genes“ is a long-standing myth broad forward by the 
initiators of the U.S. human genome sequencing projects in 1990. This large 
number completely contradicted all genetics and mutation data since the 1940th, 
but the sequencing community (genome, cDNA, EST) didn’t read even the standard 
text books. Thus, the “30,000” genes published with the two human genome papers 
in 2001 are not “surprisingly low” but just in accordance with the predictions 
and the data since the 1940th. The gene number went down to about 23,000 
already in 2004, and the current numbers (depending on database) range around 
20,000 human protein-coding genes. The myth of the large numbers is only 
propagated by those who profit from larger numbers (e.g. bigger grants, papers 
in higher IF journals, big consortia).

I have written a review about the current state (and history) of the human 
protein-coding genes, which will appear online in BioEssays soon and finally in 
the November issue (will be open access). In this review there will be some 
(hopefully) useful plots showing the gene numbers since the 1940th and a 
detailed review of all the numbers and their experimental basis (most were 
actually just extrapolations from small-scale data).

Please excuse this kind of self-advertisement, but it is really more than time 
to move this myth out of science literature and communication.

Best regards,
Martin

Priv. Doz. Dr. Martin Kollmar

Group Systems Biology of Motor Proteins
Department NMR-based Structural Biology
Max-Planck-Institute for Biophysical Chemistry
Am Fassberg 11
37077 Goettingen
Deutschland

www.motorprotein.de<http://www.motorprotein.de/> (Homepage)
www.cymobase.org<http://www.cymobase.org/> (Database of Cytoskeletal and Motor 
Proteins)
www.diark.org<http://www.diark.org/> (diArk - a resource for eukaryotic genome 
research)
www.webscipio.org<http://www.webscipio.org/> (Scipio - eukaryotic gene 
identification)

Von: CCP4 bulletin board  Im Auftrag von John R Helliwell
Gesendet: Donnerstag, 19. September 2019 08:51
An: CCP4BB@JISCMAIL.AC.UK
Betreff: Re: [ccp4bb] challenges in structural biology

Dear James,
Well, 100,000 genes used to be the estimate of the size of the human genome.
(eg see 
https://physicsworld.com/a/protein-crystallography-the-human-genome-in-3-d/ )
It seems it has got easier, albeit still gargantuan, at ~30,000 genes to be 
expressed into proteins.

Meanwhile funding agencies also look out for Big Ideas:-
https://epsrc.ukri.org/research/ourportfolio/epsrcbigideas/?utm_source=Twitter_medium=social_campaign=SocialSignIn
and even helpfully spell out the difference between a Big Idea and a Grand 
Challenge!
Maybe an “Open Door for funding” for us all?

Today also the repertoire of methods capable of resolving in 3D protein 
structures has expanded further with the splendid development of cryoEM.

To define challenges in terms of projects, as Max Perutz taught us 
(“Haemoglobin the Molecular Lung”) avoids methods looking for problems.

Also a final thought, how we organise ourselves in different areas of the World 
varies according to our cultural traditions. So the Big Project is neutral to 
politics and can accommodate all contributions however so arrived at.

“What shall we do with it?”
As Darwin taught us, first make your Collection..

Greetings!
John

Emeritus Professor John R Helliwell DSc
https://www.crcpress.com/The-Whats-of-a-Scientific-Life/Helliwell/p/book/9780367233020



On 18 Sep 2019, at 22:15, James Holton 
mailto:jmhol...@lbl.gov>> wrote:
Thank you John, an excellent choice as always.  Here is your trillion dollars!  
Now, what are you going to do with it?

Do you think simply scaling up current technology could reach this goal?  More 
screens, more combinations, more compute cycles?  Remember, if you want the 
"genome/proteome" you need all of it, including all those super-cool human 
membrane proteins we gave up on because they were too hard.

I think we all have at least one of those projects in our past.  What was the 
show-stopper in the end?  Did they just not grow crystals? Poor diffraction? 
Weird diffraction? Twinned? Won't phase? Won't refine to a decent R factor? 
Annoying reviewer? Did you try cryoEM? NMR? and did they not work either?

I think a key question for all of us is: what new capability would make you 
decide to go back and pick up your old favorite project again?  Without your 
structure, the genome is incomplete.

-James Holton
MAD Scientist
On 9/16/2019 12:24 AM, John R Helliwell wrote:
Dear James,
Here you go, a “grand challenge” suggestion to consider for funding from the 
“James Holton Foundation for structural biology research”:-
“The human genome/proteome in 3-D”
Greetings,
John
Emeritus Professor John R Helliwell DSc




On 14 Sep 2019, at 02:39, James Holton 
mailto:jmhol...@lbl.gov>> wrote:

I would like to thank everyone who took the time to respond to my question that 

Re: [ccp4bb] challenges in structural biology

[John R Helliwell]

Dear James,
Well, 100,000 genes used to be the estimate of the size of the human genome.
(eg see 
https://physicsworld.com/a/protein-crystallography-the-human-genome-in-3-d/ )
It seems it has got easier, albeit still gargantuan, at ~30,000 genes to be 
expressed into proteins.

Meanwhile funding agencies also look out for Big Ideas:-
https://epsrc.ukri.org/research/ourportfolio/epsrcbigideas/?utm_source=Twitter_medium=social_campaign=SocialSignIn
and even helpfully spell out the difference between a Big Idea and a Grand 
Challenge!
Maybe an “Open Door for funding” for us all?

Today also the repertoire of methods capable of resolving in 3D protein 
structures has expanded further with the splendid development of cryoEM. 

To define challenges in terms of projects, as Max Perutz taught us 
(“Haemoglobin the Molecular Lung”) avoids methods looking for problems.

Also a final thought, how we organise ourselves in different areas of the World 
varies according to our cultural traditions. So the Big Project is neutral to 
politics and can accommodate all contributions however so arrived at.

“What shall we do with it?”
As Darwin taught us, first make your Collection..

Greetings!
John 


Emeritus Professor John R Helliwell DSc
https://www.crcpress.com/The-Whats-of-a-Scientific-Life/Helliwell/p/book/9780367233020



> On 18 Sep 2019, at 22:15, James Holton  wrote:
> 
> Thank you John, an excellent choice as always.  Here is your trillion 
> dollars!  Now, what are you going to do with it?
> 
> Do you think simply scaling up current technology could reach this goal?  
> More screens, more combinations, more compute cycles?  Remember, if you want 
> the "genome/proteome" you need all of it, including all those super-cool 
> human membrane proteins we gave up on because they were too hard.  
> 
> I think we all have at least one of those projects in our past.  What was the 
> show-stopper in the end?  Did they just not grow crystals? Poor diffraction? 
> Weird diffraction? Twinned? Won't phase? Won't refine to a decent R factor? 
> Annoying reviewer? Did you try cryoEM? NMR? and did they not work either?
> 
> I think a key question for all of us is: what new capability would make you 
> decide to go back and pick up your old favorite project again?  Without your 
> structure, the genome is incomplete.
> 
> -James Holton
> MAD Scientist
> 
>> On 9/16/2019 12:24 AM, John R Helliwell wrote:
>> Dear James,
>> Here you go, a “grand challenge” suggestion to consider for funding from the 
>> “James Holton Foundation for structural biology research”:-
>> “The human genome/proteome in 3-D”
>> Greetings,
>> John 
>> Emeritus Professor John R Helliwell DSc
>> 
>> 
>> 
>> 
>> On 14 Sep 2019, at 02:39, James Holton  wrote:
>> 
>>> 
>>> I would like to thank everyone who took the time to respond to my question 
>>> that started this thread.  It is really good for me to get a sense of the 
>>> community perspective.  Some debates were predictable, others not.  Many 
>>> ideas I agree with, some not so much.  All were thought-provoking. I think 
>>> this is going to be a really good GRC!
>>> 
>>> Something I did not expect to distill from all the responses is that the 
>>> dominant challenge in structural biology is financial. The most common 
>>> strategy suggested for addressing this challenge was torpedoing other 
>>> scientists in similar fields, perhaps expecting to benefit from the 
>>> flotsam.  Historically, this strategy is often counterproductive and at 
>>> best inefficient. The good news is there is a lot of room for improvement. 
>>> In reality, we are all on the same ship, and the people in our funding 
>>> agencies fighting to get us what we need can be much more effective when 
>>> armed with positive ideas and clear plans.  That is a better strategy for 
>>> overcoming this challenge.
>>> 
>>> To this end, my first GRC session title is going to be:
>>> 
>>> "If I had a trillion dollars for structural biology"
>>> 
>>> I think we can all agree that science in general is vastly under-funded 
>>> relative to the impact it has on the human condition.  For example, I 
>>> estimate the value of a general cure for cancer to be at least a trillion 
>>> dollars.  This is based on the lives claimed every year, multiplied by how 
>>> much one person would gladly pay after being diagnosed (amortized over the 
>>> rest of their much longer life). This is only ~1% of the Gross World 
>>> Product, a real bargain if we can come up with a plan that will actually 
>>> work. 
>>> 
>>> Now, obviously not all cancer research is structural biology, but not all 
>>> structural biology is cancer research either. Let us suppose for a moment 
>>> that you (yes, I'm talking to YOU), were given a trillion-dollar budget to 
>>> do your science.  After buying all the tools and hiring all the people you 
>>> wanted: would that solve all of your problems?  I expect not. The 
>>> intellectual and technical challenges that remain are what I 

Re: [ccp4bb] challenges in structural biology

[James Holton]

Thank you John, an excellent choice as always.  Here is your trillion 
dollars!  Now, what are you going to do with it?


Do you think simply scaling up current technology could reach this 
goal?  More screens, more combinations, more compute cycles? Remember, 
if you want the "genome/proteome" you need all of it, including all 
those super-cool human membrane proteins we gave up on because they were 
too hard.


I think we all have at least one of those projects in our past. What was 
the show-stopper in the end?  Did they just not grow crystals? Poor 
diffraction? Weird diffraction? Twinned? Won't phase? Won't refine to a 
decent R factor? Annoying reviewer? Did you try cryoEM? NMR? and did 
they not work either?


I think a key question for all of us is: what new capability would make 
you decide to go back and pick up your old favorite project again?  
Without your structure, the genome is incomplete.


-James Holton
MAD Scientist

On 9/16/2019 12:24 AM, John R Helliwell wrote:

Dear James,
Here you go, a “grand challenge” suggestion to consider for funding 
from the “James Holton Foundation for structural biology research”:-

“The human genome/proteome in 3-D”
Greetings,
John
Emeritus Professor John R Helliwell DSc




On 14 Sep 2019, at 02:39, James Holton > wrote:




I would like to thank everyone who took the time to respond to my 
question that started this thread.  It is really good for me to get a 
sense of the community perspective.  Some debates were predictable, 
others not.  Many ideas I agree with, some not so much.  All were 
thought-provoking. I think this is going to be a really good GRC!


Something I did not expect to distill from all the responses is that 
the dominant challenge in structural biology is financial. The most 
common strategy suggested for addressing this challenge was 
torpedoing other scientists in similar fields, perhaps expecting to 
benefit from the flotsam.  Historically, this strategy is often 
counterproductive and at best inefficient. The good news is there is 
a lot of room for improvement. In reality, we are all on the same 
ship, and the people in our funding agencies fighting to get us what 
we need can be much more effective when armed with positive ideas and 
clear plans.  That is a better strategy for overcoming this challenge.


To this end, my first GRC session title is going to be:

"If I had a trillion dollars for structural biology"

I think we can all agree that science in general is vastly 
under-funded relative to the impact it has on the human condition.  
For example, I estimate the value of a general cure for cancer to be 
at least a trillion dollars.  This is based on the lives claimed 
every year, multiplied by how much one person would gladly pay after 
being diagnosed (amortized over the rest of their much longer life). 
This is only ~1% of the Gross World Product, a real bargain if we can 
come up with a plan that will actually work.


Now, obviously not all cancer research is structural biology, but not 
all structural biology is cancer research either. Let us suppose for 
a moment that you (yes, I'm talking to YOU), were given a 
trillion-dollar budget to do your science.  After buying all the 
tools and hiring all the people you wanted: would that solve all of 
your problems?  I expect not. The intellectual and technical 
challenges that remain are what I believe science is really all 
about, and the 2020 Diffraction Methods GRC will focus on the ones 
facing structural biology.


My goals here are twofold:
1) I believe it would be healthy for this field if we all spent a 
little time "thinking big"
2) I want to remove financial anxiety from the discussion, both here 
and at the GRC.


I ask for one restraint: please confine the discussion to structural 
biology.  I understand it is difficult to think about the 
trillion-dollar level without involving politics, but the CCP4 
Bulletin Board is not a political discussion forum, and neither is 
the GRC. Assume all the other worthy causes in the world are given 
their own ample budgets. This trillion is yours, and you have to 
spend it on structural biology.  If you can't think of anything, 
think harder.


To get you started, a few things that could be done for under a 
trillion dollars:
1) re-do all the protein crystallization in the PDB, 500 times 
(saving all information)
2) buy Google and Facebook, get their AI teams to do machine learning 
and structure prediction for us
3) hire every "biological scientist" in the world, and give each $1M 
to work on your projects

4) re-do the NASA Apollo program three times
5) build 1000 XFELs and 100,000 Titan microscopes (yes, that's "and")
6) solve the phase problem by brute force. (zettaflops-scale 
computing at $0.03/gflop)
7) build half a dozen terapixel detectors (ask Colin Nave what those 
can do)
8) fund every NIH grant submitted in the last 5 years. Not just the 
awarded ones, all of them.
9) X-prize style 

Re: [ccp4bb] challenges in structural biology

[John R Helliwell]

Dear James,
Here you go, a “grand challenge” suggestion to consider for funding from the 
“James Holton Foundation for structural biology research”:-
“The human genome/proteome in 3-D”
Greetings,
John 
Emeritus Professor John R Helliwell DSc




> On 14 Sep 2019, at 02:39, James Holton  wrote:
> 
> 
> I would like to thank everyone who took the time to respond to my question 
> that started this thread.  It is really good for me to get a sense of the 
> community perspective.  Some debates were predictable, others not.  Many 
> ideas I agree with, some not so much.  All were thought-provoking. I think 
> this is going to be a really good GRC!
> 
> Something I did not expect to distill from all the responses is that the 
> dominant challenge in structural biology is financial. The most common 
> strategy suggested for addressing this challenge was torpedoing other 
> scientists in similar fields, perhaps expecting to benefit from the flotsam.  
> Historically, this strategy is often counterproductive and at best 
> inefficient. The good news is there is a lot of room for improvement. In 
> reality, we are all on the same ship, and the people in our funding agencies 
> fighting to get us what we need can be much more effective when armed with 
> positive ideas and clear plans.  That is a better strategy for overcoming 
> this challenge.
> 
> To this end, my first GRC session title is going to be:
> 
> "If I had a trillion dollars for structural biology"
> 
> I think we can all agree that science in general is vastly under-funded 
> relative to the impact it has on the human condition.  For example, I 
> estimate the value of a general cure for cancer to be at least a trillion 
> dollars.  This is based on the lives claimed every year, multiplied by how 
> much one person would gladly pay after being diagnosed (amortized over the 
> rest of their much longer life). This is only ~1% of the Gross World Product, 
> a real bargain if we can come up with a plan that will actually work. 
> 
> Now, obviously not all cancer research is structural biology, but not all 
> structural biology is cancer research either. Let us suppose for a moment 
> that you (yes, I'm talking to YOU), were given a trillion-dollar budget to do 
> your science.  After buying all the tools and hiring all the people you 
> wanted: would that solve all of your problems?  I expect not. The 
> intellectual and technical challenges that remain are what I believe science 
> is really all about, and the 2020 Diffraction Methods GRC will focus on the 
> ones facing structural biology.  
> 
> My goals here are twofold: 
> 1) I believe it would be healthy for this field if we all spent a little time 
> "thinking big"
> 2) I want to remove financial anxiety from the discussion, both here and at 
> the GRC.
> 
> I ask for one restraint: please confine the discussion to structural biology. 
>  I understand it is difficult to think about the trillion-dollar level 
> without involving politics, but the CCP4 Bulletin Board is not a political 
> discussion forum, and neither is the GRC. Assume all the other worthy causes 
> in the world are given their own ample budgets. This trillion is yours, and 
> you have to spend it on structural biology.  If you can't think of anything, 
> think harder.
> 
> To get you started, a few things that could be done for under a trillion 
> dollars:
> 1) re-do all the protein crystallization in the PDB, 500 times (saving all 
> information)
> 2) buy Google and Facebook, get their AI teams to do machine learning and 
> structure prediction for us
> 3) hire every "biological scientist" in the world, and give each $1M to work 
> on your projects
> 4) re-do the NASA Apollo program three times
> 5) build 1000 XFELs and 100,000 Titan microscopes (yes, that's "and")
> 6) solve the phase problem by brute force.  (zettaflops-scale computing at 
> $0.03/gflop)
> 7) build half a dozen terapixel detectors (ask Colin Nave what those can do)
> 8) fund every NIH grant submitted in the last 5 years. Not just the awarded 
> ones, all of them.
> 9) X-prize style competitions for landmark achievements, such as predicting 
> crystallization outcomes, or finding a universal way to stop protein from 
> denaturing on the air-water interface.
> 
> This is not a to-do list, but rather an attempt to convey the scale of what 
> can be done.  Oh, and you have a month or so to think about it. The meeting 
> is July 26-31 2020, but my speaker list is due Oct 15.
> 
> Now, of course, at the GRC I will not actually have billion-dollar prizes to 
> pass around, but I do want to set our sights on those lofty goals, and then 
> work on the bridge we will need to get there.
> 
> So, when I say "challenge" I mean more than something we all agree is hard.  
> Those would make for very short talks.  I am after something more like a 
> benchmark.  Useful challenges should have certain properties.  They should be:
> a) possible, because something that doesn't work 

Re: [ccp4bb] challenges in structural biology

[James Holton]

I would like to thank everyone who took the time to respond to my 
question that started this thread.  It is really good for me to get a 
sense of the community perspective.  Some debates were predictable, 
others not.  Many ideas I agree with, some not so much.  All were 
thought-provoking. I think this is going to be a really good GRC!


Something I did not expect to distill from all the responses is that the 
dominant challenge in structural biology is financial. The most common 
strategy suggested for addressing this challenge was torpedoing other 
scientists in similar fields, perhaps expecting to benefit from the 
flotsam.  Historically, this strategy is often counterproductive and at 
best inefficient. The good news is there is a lot of room for 
improvement. In reality, we are all on the same ship, and the people in 
our funding agencies fighting to get us what we need can be much more 
effective when armed with positive ideas and clear plans.  That is a 
better strategy for overcoming this challenge.


To this end, my first GRC session title is going to be:

"If I had a trillion dollars for structural biology"

I think we can all agree that science in general is vastly under-funded 
relative to the impact it has on the human condition. For example, I 
estimate the value of a general cure for cancer to be at least a 
trillion dollars.  This is based on the lives claimed every year, 
multiplied by how much one person would gladly pay after being diagnosed 
(amortized over the rest of their much longer life). This is only ~1% of 
the Gross World Product, a real bargain if we can come up with a plan 
that will actually work.


Now, obviously not all cancer research is structural biology, but not 
all structural biology is cancer research either. Let us suppose for a 
moment that you (yes, I'm talking to YOU), were given a trillion-dollar 
budget to do your science.  After buying all the tools and hiring all 
the people you wanted: would that solve all of your problems?  I expect 
not. The intellectual and technical challenges that remain are what I 
believe science is really all about, and the 2020 Diffraction Methods 
GRC will focus on the ones facing structural biology.


My goals here are twofold:
1) I believe it would be healthy for this field if we all spent a little 
time "thinking big"
2) I want to remove financial anxiety from the discussion, both here and 
at the GRC.


I ask for one restraint: please confine the discussion to structural 
biology.  I understand it is difficult to think about the 
trillion-dollar level without involving politics, but the CCP4 Bulletin 
Board is not a political discussion forum, and neither is the GRC. 
Assume all the other worthy causes in the world are given their own 
ample budgets. This trillion is yours, and you have to spend it on 
structural biology.  If you can't think of anything, think harder.


To get you started, a few things that could be done for under a trillion 
dollars:
1) re-do all the protein crystallization in the PDB, 500 times (saving 
all information)
2) buy Google and Facebook, get their AI teams to do machine learning 
and structure prediction for us
3) hire every "biological scientist" in the world, and give each $1M to 
work on your projects

4) re-do the NASA Apollo program three times
5) build 1000 XFELs and 100,000 Titan microscopes (yes, that's "and")
6) solve the phase problem by brute force.  (zettaflops-scale computing 
at $0.03/gflop)

7) build half a dozen terapixel detectors (ask Colin Nave what those can do)
8) fund every NIH grant submitted in the last 5 years. Not just the 
awarded ones, all of them.
9) X-prize style competitions for landmark achievements, such as 
predicting crystallization outcomes, or finding a universal way to stop 
protein from denaturing on the air-water interface.


This is not a to-do list, but rather an attempt to convey the scale of 
what can be done.  Oh, and you have a month or so to think about it. The 
meeting is July 26-31 2020, but my speaker list is due Oct 15.


Now, of course, at the GRC I will not actually have billion-dollar 
prizes to pass around, but I do want to set our sights on those lofty 
goals, and then work on the bridge we will need to get there.


So, when I say "challenge" I mean more than something we all agree is 
hard.  Those would make for very short talks.  I am after something more 
like a benchmark.  Useful challenges should have certain properties.  
They should be:
a) possible, because something that doesn't work no matter what you do 
is no fun.

b) hard, because something that is too easy is also not very interesting
c) realistic, as in relevant to a real-world problem we all agree is 
important

d) accessible, as in reasonable download sizes and/or affordable reagents
e) fast, because it if takes forever to try it nobody will have time to 
participate

f) measurable, as in having a clear and broadly acceptable "score"
g) adjustable, as in the level of 

Re: [ccp4bb] challenges in structural biology

[Gloria Borgstahl]

Sorry to be late chiming in on this post (survived RAGBRAI).  I think the
challenges (crystallization, perdeuteration) and benefits of neutron
crystallography (where are those protons) could be included.  We are now in
an era of using cryotrapping with neutrons which I think is really cutting
edge for time-resolved structural information.  My two cents, G

On Mon, Jul 22, 2019 at 1:55 AM Kay Diederichs <
kay.diederi...@uni-konstanz.de> wrote:

> Dear Artem, Tom, Janet,
>
> for me and probably others the usage of words like 'magic bullet' (which
> you defend, or try to redefine) implies a belief-based esoteric approach
> that has little to do with science. I suggest that to obtain funding,
> 'magic bullets' should not be promised, because these cannot be delivered
> (I gave the lo-gravity hi-funding example).
>
> That this discussion (including messages by Janet and Tom) happens at all
> suggests that crystallization is currently not a science - it lacks a
> consistent nomenclature and way of documentation, and suffers from strong
> publication bias (many unpublished negative results).
>
> On the other hand, what you (Janet, Tom) write about the research that
> should/could be performed - this sounds a lot like a scientific approach,
> and is not different from what has been realized in other areas of
> crystallography. Yes, existing tools for predicting crystallization success
> are not consulted because the rate of false positives and false negatives
> is high. If those rates could be reproducibly reduced, I bet the usage
> would go up - that could start a feedback loop leading to even better
> predictions. Is work in this direction sexy? No. Is it useful? Yes. Is it
> hard work? Yes. Does it contribute to make crystallization a science? Yes.
>
> What about 'deep learning' applied to crystallization outcomes? Can it
> guide individual trials better than intuition? Can it find previously
> unknown promising combinations on a larger scale?
>
> Can this be funded? Yes of course. Your statement that crystallization
> gets no funding may be true in some countries (but aren't CCP4BB readers
> from the U.S. also reviewers?), but it's untrue in others - think of groups
> in France that obviously got long-term funding. And for space (low-gravity)
> - that amount of funding could have been used for a lot of meaningful
> earth-bound research.
>
> Kay
>
>
> Am 21.07.19 um 23:04 schrieb Artem Evdokimov:
> > Dear Kay
> >
> >
> > I disagree that 'magic bullet' is impossible. I think the definition is
> wrong here - magic bullet to me is a rational set of methods that (when
> executed with precision and care) enable crystallization to the maximum
> possible benefit. This includes everything - constructs, crystallization
> design, etc. Part of the magic bullet is also a precise knowledge when
> crystallization is unlikely (i.e. an actual proven predictor that
> consistently discriminates between "you're going to succeed if you work
> hard" and "it's doomed to fail, don't bother" scenarios in crystallization.
> >
> > The above is not sexy. It does not present itself as a lovely subject on
> which to have international cocktail parties with politicians delivering
> fancy speeches. But that is what is needed, and no one is funding that to
> the best of my knowledge.
> >
> > What needs to be done is a significant amount of testing,
> standardization, and methods development from the perspective of holistic
> outcome (i.e. crystals that work) - and none of the previously advertised
> 'magic bullets' work the way I just described.
> >
> > Having written this, I think you're right - this is a bit of a
> distraction from James' original point. However it's a valid opportunity
> for a lively discussion on its own :)
> >
> > Artem
> >
> > - Cosmic Cats approve of this message
> >
> >
> > On Sun, Jul 21, 2019 at 4:52 PM Kay Diederichs <
> kay.diederi...@uni-konstanz.de >
> wrote:
> >
> > Dear Artem,
> >
> > black or white is not my way of thinking, which is why I don't
> believe in Hannibal's approach when it comes to crystallization.
> >
> > None of the magic bullets that were advertised over the past decades
> have proven generally applicable.  I believe more in incremental
> improvement which in this case includes a few biophysical characterization
> methods, possibly improved microfluidics or other apparatus, and expanded
> screens. And a lot of hard work, perseverance, intuition, frustration
> >  tolerance. Nothing that really needs huge funding - of course it
> does need money, but just a  share of what is anyway needed for the usual
> lab work including expression, purification, functional characterization,
> binding studies and the like.
> >
> > One area where a huge amount of money was burnt is crystallization
> in space, on board of e.g. the spacelab and ISS. This is for me an example
> of a mis-led approach to throw money at a difficult problem, with the
> 

Re: [ccp4bb] challenges in structural biology

[CCP4BB]

Hi

It's pretty much what the powder people do when using Rietveld refinement, 
isn't it? As far as I know, they fit a calculated curve from their structure to 
a 1D trace of the powder pattern (happy to be corrected on this). All you need 
to do is extend this to 3D - there may be enough work there for a project 
student ;-).

Harry
--
Dr Harry Powell

> On 30 Jul 2019, at 10:47, Loes Kroon-Batenburg  
> wrote:
> 
> Dear Jacob,
> 
> That should indeed be our ultimate goal: refining against the image data 
> rather than against process data. This would require a good model for the 
> crystal, mosaicity being an important parameter in this, and for the internal 
> variation in the molecular structure. Modelling the Bragg spots is what we do 
> currently wth EVAL.  James Holton is doing also this with nanoBragg. 
> Unfortunately we would also have to simulate solvent rings etc. 
> 
> Best wishes,
> Loes
>> On 07/25/19 19:07, Keller, Jacob wrote:
>> >>It would seem to me that an important issue is also: do get all 
>> >>information out of our diffraction data? By integrating the Bragg peaks we 
>> >>usually neglect the diffuse scattering that could potentially contain 
>> >>additional (dynamic) structural information. This can be cloudy diffuse 
>> >>scattering hidden in the background but also diffuse streaks that contain 
>> >>information on packing disorder and reveals intrinsic interactions in the 
>> >>crystal.
>> 
>> Along these lines, and taking a page from you also, how about 
>> “crystallographic model refinement as image-faking?” Metrics of the goodness 
>> of a particular refinement could simply be some measure of the correlation 
>> between predicted vs. measured images. I have seen some of this done with 
>> diffuse scattering, but why not with the whole thing, including intensity 
>> and shape of Bragg peaks, solvent rings, etc? Maybe instead of doing the 
>> multiple steps of (indexing, integration, scaling, solving…) all of this 
>> could be refined as one? Processing parameters like moscaicity [sic] etc 
>> would now be part of the final model…?
>>  
>> JPK
>>  
>>  
>>  
>> 
>> Loes Kroon-Batenburg
>> 
>> On 07/15/19 21:44, Holton, James M wrote:
>> Hello folks,
>>  
>> I have the distinct honor of chairing the next Gordon Research 
>> Conference on Diffraction Methods in Structural Biology (July 26-31 
>> 2020).  This meeting will focus on the biggest challenges currently 
>> faced by structural biologists, and I mean actual real-world 
>> challenges.  As much as possible, these challenges will take the form of 
>> friendly competitions with defined parameters, data, a scoring system, 
>> and "winners", to be established along with other unpublished results 
>> only at the meeting, as is tradition at GRCs.
>>  
>> But what are the principle challenges in biological structure 
>> determination today?  I of course have my own ideas, but I feel like I'm 
>> forgetting something.  Obvious choices are:
>> 1) getting crystals to diffract better
>> 2) building models into low-resolution maps (after failing at #1)
>> 3) telling if a ligand is really there or not
>> 4) the phase problem (dealing with weak signal, twinning and 
>> pseudotranslation)
>> 5) what does "resolution" really mean?
>> 6) why are macromolecular R factors so much higher than small-molecule ones?
>> 7) what is the best way to process serial crystallography data?
>> 8) how should one deal with non-isomorphism in multi-crystal methods?
>> 9) what is the "structure" of something that won't sit still?
>>  
>> What am I missing?  Is industry facing different problems than 
>> academics?  Are there specific challenges facing electron-based 
>> techniques?  If so, could the combined strength of all the world's 
>> methods developers solve them?  I'm interested in hearing the voice of 
>> this community.  On or off-list is fine.
>>  
>> -James Holton
>> MAD Scientist
>>  
>>  
>> 
>>  
>> To unsubscribe from the CCP4BB list, click the following link:
>> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1
>> 
>> 
>> 
>> -- 
>>  
>> __
>>  
>> Dr. Loes Kroon-Batenburg
>> Dept. of Crystal and Structural Chemistry
>> Bijvoet Center for Biomolecular Research
>> Utrecht University
>> Padualaan 8, 3584 CH Utrecht
>> The Netherlands
>>  
>> E-mail : l.m.j.kroon-batenb...@uu.nl
>> phone  : +31-30-2532865
>> fax: +31-30-2533940
>> __ 
>>  
>> To unsubscribe from the CCP4BB list, click the following link:
>> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1
>> 
> 
> 
> -- 
> 
> __
> 
> Dr. Loes Kroon-Batenburg
> Dept. of Crystal and Structural Chemistry
> Bijvoet Center for Biomolecular Research
> Utrecht University
> Padualaan 8, 3584 CH Utrecht
> The Netherlands
> 
> E-mail : l.m.j.kroon-batenb...@uu.nl
> phone  : +31-30-2532865
> 

Re: [ccp4bb] challenges in structural biology

[Kroon-Batenburg, L.M.J. (Loes)]

Dear James,

It would seem to me that an important issue is also: do get all information out 
of our diffraction data? By integrating the Bragg peaks we usually neglect the 
diffuse scattering that could potentially contain additional (dynamic) 
structural information. This can be cloudy diffuse scattering hidden in the 
background but also diffuse streaks that contain information on packing 
disorder and reveals intrinsic interactions in the crystal.

Loes Kroon-Batenburg

On 07/15/19 21:44, Holton, James M wrote:

Hello folks,

I have the distinct honor of chairing the next Gordon Research
Conference on Diffraction Methods in Structural Biology (July 26-31
2020).  This meeting will focus on the biggest challenges currently
faced by structural biologists, and I mean actual real-world
challenges.  As much as possible, these challenges will take the form of
friendly competitions with defined parameters, data, a scoring system,
and "winners", to be established along with other unpublished results
only at the meeting, as is tradition at GRCs.

But what are the principle challenges in biological structure
determination today?  I of course have my own ideas, but I feel like I'm
forgetting something.  Obvious choices are:
1) getting crystals to diffract better
2) building models into low-resolution maps (after failing at #1)
3) telling if a ligand is really there or not
4) the phase problem (dealing with weak signal, twinning and
pseudotranslation)
5) what does "resolution" really mean?
6) why are macromolecular R factors so much higher than small-molecule ones?
7) what is the best way to process serial crystallography data?
8) how should one deal with non-isomorphism in multi-crystal methods?
9) what is the "structure" of something that won't sit still?

What am I missing?  Is industry facing different problems than
academics?  Are there specific challenges facing electron-based
techniques?  If so, could the combined strength of all the world's
methods developers solve them?  I'm interested in hearing the voice of
this community.  On or off-list is fine.

-James Holton
MAD Scientist




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--

__

Dr. Loes Kroon-Batenburg
Dept. of Crystal and Structural Chemistry
Bijvoet Center for Biomolecular Research
Utrecht University
Padualaan 8, 3584 CH Utrecht
The Netherlands

E-mail : l.m.j.kroon-batenb...@uu.nl
phone  : +31-30-2532865
fax: +31-30-2533940
__



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Re: [ccp4bb] challenges in structural biology

[Patrick Shaw Stewart]

I have regularly been struck by how closely related proteins crystallize in
completely different conditions. Eg see Galina Obmolova and colleagues'
excellent paper (ref below).  A set of sixteen highly homologous Fabs were
crystallized in apparently random conditions.  Roughly half used PEG, half
high-salt conditions, salts used included sulfate (sic!), formate, citrate,
acetate, tartrate, chloride etc etc, while pHs ranged from 4.5 to 9.5.

I also once downloaded the entire PDB and looked for correlations between
the reported crystallization conditions and the (summed) areas of every
atom of every residue on the surface of the proteins.  I came up with . . .
hmm  . . absolutely nothing useful.

I conclude that we need to start with regular screening for pretty much
every new sample that we have - so an unbiased empirical approach is the
only good way to go.

Thx Patrick


Galina ref - Obmolova, G., et al. "Protein crystallization with microseed
matrix screening: application to human germline antibody Fabs." *Acta
Crystallographica Section F: Structural Biology Communications* 70.8
(2014): 1107-1115.



On Tue, 23 Jul 2019, 23:53 Newman, Janet (Manufacturing, Parkville),
 wrote:

> There are a bunch of people doing this – in the small molecule world. And
> a lot of work has been done on some very robust protein systems too. Can
> you guess which ones?
>
>
>
> The real issue (at the moment) is that all the pre-work needed to predict
> if or how a protein might crystallise takes more work and more protein than
> setting up crystallisation experiments.
>
> How many people do DSL on protein in a crystallisation screen, for
> example? Or do self-association chromatography to determine the B22 (which
> changes under different conditions, naturally). Or try mapping out a phase
> diagram (for each condition)?
>
>
>
> Many people are not even aware that a simple PCT can help one work out a
> sensible starting concentration for crystallisation trials.
>
>
>
> As for AI, at the moment unsupervised learning doesn’t seem to do much,
> which means we need vast, well annotated datasets to make progress. MARKO,
> which Sarah mentioned, required half a million scored images, which took
> years to get together.
>
>
>
> Janet
>
>
>
> *From:* CCP4 bulletin board  *On Behalf Of *Keller,
> Jacob
> *Sent:* Wednesday, 24 July 2019 4:18 AM
> *To:* CCP4BB@JISCMAIL.AC.UK
> *Subject:* Re: [ccp4bb] challenges in structural biology
>
>
>
> What about developing a theory of how crystallization happens, i.e., what
> does the microscopic “picture” look like when crystals are forming, then
> predicting based on that picture? I remember looking into these things
> about ten years ago, and there were some cool things being done with
> various scattering methods and with AFM, but am not sure now what is the
> state of that art.
>
>
>
> It would seem to me that crystallization is the search for intermolecular
> docking sites of sufficiently good (albeit presumably weak) affinity and
> consistent with the formation of a 3D lattice. I wonder what the affinity
> of these sites is, actually—I guess somewhere in the micromolar range,
> based on usual protein concentrations under crystallization conditions (10
> mg/ml of a 40 kD protein is 250 uM).
>
>
>
> Presumably the various docking sites would change affinity based on the
> crystallization conditions, which would explain why some crystallization
> conditions work, others don’t?
>
>
>
> Maybe a systematic look at all crystallization contacts in the PDB might
> yield some insight into crystallization? Maybe it’s already been done?
>
>
>
> JPK
>
>
> --
>
> To unsubscribe from the CCP4BB list, click the following link:
> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1
>
> --
>
> To unsubscribe from the CCP4BB list, click the following link:
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>



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Re: [ccp4bb] challenges in structural biology

[Hargreaves, David]

Dear CCP4bb,

From my industrial perspective: The crystallisation bottleneck has probably 
been fairly well addressed. High throughput screening using robotics and around 
20ul of protein per screen is common. There are lots of screens to try even if 
they are rather redundant in their content. However, I feel there are two 
things missing: high throughput protein production at microscale and specific 
tools for construct design. Generally, industry is interested in the druggable 
site which perhaps is only one domain of a multidomain target protein. Getting 
a suitably robust crystal system often requires more than one iteration of 
multiple construct design which in my experience is something of a lottery. 
Some helpful design tools and an order of magnitude increase in the number of 
constructs that can be delivered from protein supply would help.

Best wishes,

David


Dr. David Hargreaves
Associate Principal Scientist
_
AstraZeneca
Discovery Sciences, Structure & Biophysics
Dr David Hargreaves.
Office R1-09/Lab FL54
AstraZeneca Darwin Building
Unit 310
Cambridge Science Park
Milton Road
Cambridge
CB4 0WG

telephone: +441223223546

David.Hargreaves @astrazeneca.com

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Re: [ccp4bb] challenges in structural biology

[Patrick Shaw Stewart]

I take the view that I'm trying to communicate with as many people as
possible, without distracting them with my spelling . . . So go for US
spellings.

Sent from mobile

On Tue, 23 Jul 2019, 22:39 Goldman, Adrian, 
wrote:

> ..and responding in the same vein:
>
> my OED says that its etymology also comes from the Latin sulfur, sulphura
> in the plural.  So there is an etymological basis for the ph, even if it
> doesn’t come from Greek.
>
> Plus, since when has etymological logic has _anything_ to do with English
> spelling?
>
> Finally, it may be how the RSC is spelling it, but I would take a fair bet
> that writers of English prose today (pace America), contemplating an stinky
> inferno, will write “sulphurous flames”, not the unattractive and less
> stinky “sulfurous ones”.
>
> Adrian
>
>
> On 23 Jul 2019, at 22:21, CCP4BB <
> 193323b1e616-dmarc-requ...@jiscmail.ac.uk> wrote:
>
> Hi
>
> Going off at a tangent...
>
> The accepted spelling by the Royal Society of Chemistry (i.e. the
> professional body representing chemists in the U.K.) since at least the
> early 1990s has been "sulfate" too. "Sulphur", etc, has been deprecated for
> quite some time. Why? Well, there's no good etymological reason for the
> "ph" in "sulphate". My 1984 copy of Greenwood and Earnshaw's "Chemistry of
> the Elements", written in Yorkshire, uses "sulfur" etc throughout.
>
> "Phosphorus" comes from the Greek, so retains the "ph"s on both sides of
> the pond.
>
> Element 13 appears to have started life as "alumium", mutated to
> "aluminum", and finally (in the English speaking world outside North
> America) settled down as "aluminium".
>
> Harry
> --
> Dr Harry Powell
>
> On 23 Jul 2019, at 17:12, Engin Özkan  wrote:
>
> On 7/23/19 3:35 AM, melanie.voll...@diamond.ac.uk wrote:
>
> No longer those 20 odd names for ammonium sulphate
>
>
> You mean ammonium *sulfate*. As it is called across the pond. :)
>
> On a related note on common nomenclature for recording crystallization
> experiments that Janet brought up:
>
> I find it odd that we still do not report cryo-protection methods and
> conditions in PDB depositions. Given that a large fraction of the small
> molecules observed in crystal structures are derived from the
> cryo-protectants, one would think that reporting the contents of that
> solution (and pH) would be paramount to a PDB deposition. Surely, the
> crystallographic experiment has changed since 1990/use of synchrotron
> sources, which PDB has adjusted well to in most other aspects (e.g.,
> including reporting of synchrotron x-ray optics and all the new
> detectors during submission).
>
> Engin
>
>
> 
>
> To unsubscribe from the CCP4BB list, click the following link:
> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1
>
>
> --
>
> To unsubscribe from the CCP4BB list, click the following link:
> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1
>
>
>
> --
>
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>



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Re: [ccp4bb] challenges in structural biology

[Newman, Janet (Manufacturing, Parkville)]

There are a bunch of people doing this – in the small molecule world. And a lot 
of work has been done on some very robust protein systems too. Can you guess 
which ones?

The real issue (at the moment) is that all the pre-work needed to predict if or 
how a protein might crystallise takes more work and more protein than setting 
up crystallisation experiments.
How many people do DSL on protein in a crystallisation screen, for example? Or 
do self-association chromatography to determine the B22 (which changes under 
different conditions, naturally). Or try mapping out a phase diagram (for each 
condition)?

Many people are not even aware that a simple PCT can help one work out a 
sensible starting concentration for crystallisation trials.

As for AI, at the moment unsupervised learning doesn’t seem to do much, which 
means we need vast, well annotated datasets to make progress. MARKO, which 
Sarah mentioned, required half a million scored images, which took years to get 
together.

Janet

From: CCP4 bulletin board  On Behalf Of Keller, Jacob
Sent: Wednesday, 24 July 2019 4:18 AM
To: CCP4BB@JISCMAIL.AC.UK
Subject: Re: [ccp4bb] challenges in structural biology

What about developing a theory of how crystallization happens, i.e., what does 
the microscopic “picture” look like when crystals are forming, then predicting 
based on that picture? I remember looking into these things about ten years 
ago, and there were some cool things being done with various scattering methods 
and with AFM, but am not sure now what is the state of that art.

It would seem to me that crystallization is the search for intermolecular 
docking sites of sufficiently good (albeit presumably weak) affinity and 
consistent with the formation of a 3D lattice. I wonder what the affinity of 
these sites is, actually—I guess somewhere in the micromolar range, based on 
usual protein concentrations under crystallization conditions (10 mg/ml of a 40 
kD protein is 250 uM).

Presumably the various docking sites would change affinity based on the 
crystallization conditions, which would explain why some crystallization 
conditions work, others don’t?

Maybe a systematic look at all crystallization contacts in the PDB might yield 
some insight into crystallization? Maybe it’s already been done?

JPK



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Re: [ccp4bb] challenges in structural biology

[Peat, Tom (Manufacturing, Parkville)]

Yes, but are we poets or scientists?
Wax lyrical in your poetry, but maybe have some standards in our science?
cheers, tom

Tom Peat
Proteins Group
Biomedical Program, CSIRO
343 Royal Parade
Parkville, VIC, 3052
+613 9662 7304
+614 57 539 419
tom.p...@csiro.au


From: CCP4 bulletin board  on behalf of Goldman, Adrian 

Sent: Wednesday, July 24, 2019 7:39 AM
To: CCP4BB@JISCMAIL.AC.UK 
Subject: Re: [ccp4bb] challenges in structural biology

..and responding in the same vein:

my OED says that its etymology also comes from the Latin sulfur, sulphura in 
the plural.  So there is an etymological basis for the ph, even if it doesn’t 
come from Greek.

Plus, since when has etymological logic has _anything_ to do with English 
spelling?

Finally, it may be how the RSC is spelling it, but I would take a fair bet that 
writers of English prose today (pace America), contemplating an stinky inferno, 
will write “sulphurous flames”, not the unattractive and less stinky “sulfurous 
ones”.

Adrian


On 23 Jul 2019, at 22:21, CCP4BB 
<193323b1e616-dmarc-requ...@jiscmail.ac.uk<mailto:193323b1e616-dmarc-requ...@jiscmail.ac.uk>>
 wrote:

Hi

Going off at a tangent...

The accepted spelling by the Royal Society of Chemistry (i.e. the professional 
body representing chemists in the U.K.) since at least the early 1990s has been 
"sulfate" too. "Sulphur", etc, has been deprecated for quite some time. Why? 
Well, there's no good etymological reason for the "ph" in "sulphate". My 1984 
copy of Greenwood and Earnshaw's "Chemistry of the Elements", written in 
Yorkshire, uses "sulfur" etc throughout.

"Phosphorus" comes from the Greek, so retains the "ph"s on both sides of the 
pond.

Element 13 appears to have started life as "alumium", mutated to "aluminum", 
and finally (in the English speaking world outside North America) settled down 
as "aluminium".

Harry
--
Dr Harry Powell

On 23 Jul 2019, at 17:12, Engin Özkan 
mailto:eoz...@uchicago.edu>> wrote:

On 7/23/19 3:35 AM, 
melanie.voll...@diamond.ac.uk<mailto:melanie.voll...@diamond.ac.uk> wrote:
No longer those 20 odd names for ammonium sulphate

You mean ammonium *sulfate*. As it is called across the pond. :)

On a related note on common nomenclature for recording crystallization
experiments that Janet brought up:

I find it odd that we still do not report cryo-protection methods and
conditions in PDB depositions. Given that a large fraction of the small
molecules observed in crystal structures are derived from the
cryo-protectants, one would think that reporting the contents of that
solution (and pH) would be paramount to a PDB deposition. Surely, the
crystallographic experiment has changed since 1990/use of synchrotron
sources, which PDB has adjusted well to in most other aspects (e.g.,
including reporting of synchrotron x-ray optics and all the new
detectors during submission).

Engin




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Re: [ccp4bb] challenges in structural biology

[Goldman, Adrian]

..and responding in the same vein:

my OED says that its etymology also comes from the Latin sulfur, sulphura in 
the plural.  So there is an etymological basis for the ph, even if it doesn’t 
come from Greek.

Plus, since when has etymological logic has _anything_ to do with English 
spelling?

Finally, it may be how the RSC is spelling it, but I would take a fair bet that 
writers of English prose today (pace America), contemplating an stinky inferno, 
will write “sulphurous flames”, not the unattractive and less stinky “sulfurous 
ones”.

Adrian


On 23 Jul 2019, at 22:21, CCP4BB 
<193323b1e616-dmarc-requ...@jiscmail.ac.uk>
 wrote:

Hi

Going off at a tangent...

The accepted spelling by the Royal Society of Chemistry (i.e. the professional 
body representing chemists in the U.K.) since at least the early 1990s has been 
"sulfate" too. "Sulphur", etc, has been deprecated for quite some time. Why? 
Well, there's no good etymological reason for the "ph" in "sulphate". My 1984 
copy of Greenwood and Earnshaw's "Chemistry of the Elements", written in 
Yorkshire, uses "sulfur" etc throughout.

"Phosphorus" comes from the Greek, so retains the "ph"s on both sides of the 
pond.

Element 13 appears to have started life as "alumium", mutated to "aluminum", 
and finally (in the English speaking world outside North America) settled down 
as "aluminium".

Harry
--
Dr Harry Powell

On 23 Jul 2019, at 17:12, Engin Özkan 
mailto:eoz...@uchicago.edu>> wrote:

On 7/23/19 3:35 AM, 
melanie.voll...@diamond.ac.uk wrote:
No longer those 20 odd names for ammonium sulphate

You mean ammonium *sulfate*. As it is called across the pond. :)

On a related note on common nomenclature for recording crystallization
experiments that Janet brought up:

I find it odd that we still do not report cryo-protection methods and
conditions in PDB depositions. Given that a large fraction of the small
molecules observed in crystal structures are derived from the
cryo-protectants, one would think that reporting the contents of that
solution (and pH) would be paramount to a PDB deposition. Surely, the
crystallographic experiment has changed since 1990/use of synchrotron
sources, which PDB has adjusted well to in most other aspects (e.g.,
including reporting of synchrotron x-ray optics and all the new
detectors during submission).

Engin




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Re: [ccp4bb] challenges in structural biology

[CCP4BB]

Hi

Going off at a tangent...

The accepted spelling by the Royal Society of Chemistry (i.e. the professional 
body representing chemists in the U.K.) since at least the early 1990s has been 
"sulfate" too. "Sulphur", etc, has been deprecated for quite some time. Why? 
Well, there's no good etymological reason for the "ph" in "sulphate". My 1984 
copy of Greenwood and Earnshaw's "Chemistry of the Elements", written in 
Yorkshire, uses "sulfur" etc throughout.

"Phosphorus" comes from the Greek, so retains the "ph"s on both sides of the 
pond.

Element 13 appears to have started life as "alumium", mutated to "aluminum", 
and finally (in the English speaking world outside North America) settled down 
as "aluminium".

Harry
--
Dr Harry Powell

> On 23 Jul 2019, at 17:12, Engin Özkan  wrote:
> 
>> On 7/23/19 3:35 AM, melanie.voll...@diamond.ac.uk wrote:
>> No longer those 20 odd names for ammonium sulphate
> 
> You mean ammonium *sulfate*. As it is called across the pond. :)
> 
> On a related note on common nomenclature for recording crystallization 
> experiments that Janet brought up:
> 
> I find it odd that we still do not report cryo-protection methods and 
> conditions in PDB depositions. Given that a large fraction of the small 
> molecules observed in crystal structures are derived from the 
> cryo-protectants, one would think that reporting the contents of that 
> solution (and pH) would be paramount to a PDB deposition. Surely, the 
> crystallographic experiment has changed since 1990/use of synchrotron 
> sources, which PDB has adjusted well to in most other aspects (e.g., 
> including reporting of synchrotron x-ray optics and all the new 
> detectors during submission).
> 
> Engin
> 
> 
> 
> 
> To unsubscribe from the CCP4BB list, click the following link:
> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1



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Re: [ccp4bb] challenges in structural biology

[Mark J van Raaij]

A recent paper in my favourite journal :-) suggests there is no correlation in 
crystallisation conditions even for similar proteins:
http://scripts.iucr.org/cgi-bin/paper?S2053230X19000141 
<http://scripts.iucr.org/cgi-bin/paper?S2053230X19000141>
As you write, surface loops are likely to be different even for similar 
proteins and those are likely to be important for crystal contacts.



> On 23 Jul 2019, at 10:35, melanie.voll...@diamond.ac.uk 
>  wrote:
> 
> I don't think AI will do our job in future as it heavily relies on the 
> crystal structures for training. However, as a community we should embrace 
> this technology/method to help us solve our structures. And why not start 
> with crystallisation? And again the PDB is in a good position here to enforce 
> standards which will pave the way to make use of all the information in the 
> database to train AI. All chemicals must be IUPAC conform an then the PDB can 
> decide about trivial names based on a set of rules for humans (AI doesn't 
> care how you name it as long as it is consistent). No longer those 20 odd 
> names for ammonium sulphate as Janet pointed out years ago.
> 
> 
> And regarding a magic bullet (as in one size fits all), why should a kinase 
> crystallise in the same condition as a polymerase? They do different jobs in 
> a different micro-environment within the cell so their chemical properties 
> will be different. Perhaps there could be some common ground for evolutionary 
> related molecules but a conserved active site doesn't mean a similar surface 
> for crystal contacts which is the key bit in crystallisation, right?
> 
> 


> But as Kay pointed out, crystallisation is a whole field on its own and will 
> go beyond the GRC and the question asked by James.
> 
> 
> M
> 
> 
> From: CCP4 bulletin board  on behalf of Kay Diederichs 
> 
> Sent: 23 July 2019 08:59:10
> To: ccp4bb
> Subject: Re: [ccp4bb] challenges in structural biology
> 
> If you look at the nice figure at the top of the online article, do you 
> believe that this (or rather, the correct) arrangement of domains/ molecules 
> can be predicted from a couple of correlated mutations, and energy 
> minimization? I think AI is a long way from that.  Finding the correct fold 
> of a compact domain, yes I think it's getting there.
> 
> best,
> Kay
> 
> 
> On Tue, 23 Jul 2019 08:28:42 +0530, Nishant Varshney  wrote:
> 
>> What about AI doing our job in the future?
>> 
>> https://www.nature.com/articles/d41586-019-01357-6?utm_source=Nature+Briefing_campaign=4c1d57fdf3-briefing-dy-20190722_medium=email_term=0_c9dfd39373-4c1d57fdf3-44201949
>> 
>> Best Regards
>> Nishant
>> 
>> On Mon, 22 Jul 2019 at 11:30 PM, Sarah Bowman 
>> wrote:
>> 
>>> I'd like to point out that the MAchine Recognition of Crystallization
>>> Outcomes (MARCO) makes a start to 'deep learning applied to crystallization
>>> outcomes', at least in terms of being able to classify drop images
>>> efficiently.
>>> 
>>> 
>>> 
>>> There is obviously more work to be done to correlate these data with
>>> crystallization cocktail components (which Janet and Tom point out the
>>> difficulties with) and positive outcomes.  It seems the first step really
>>> needs to be consistent descriptions and vocabulary - I fully agree with
>>> Janet here!
>>> 
>>> 
>>> 
>>> Reference on MARCO for those interested: Bruno AE, Charbonneau P, Newman
>>> J, Snell EH, So DR, Vanhoucke V, et al. (2018) Classification of
>>> crystallization outcomes using deep convolutional neural networks. PLoS ONE
>>> 13(6): e0198883. https://doi.org/10.1371/journal.pone.0198883
>>> 
>>> 
>>> 
>>> Cheers,
>>> 
>>> Sarah
>>> 
>>> 
>>> 
>>> *Sarah EJ Bowman, PhD*
>>> 
>>> 
>>> 
>>> Associate Research Scientist, Hauptman-Woodward Medical Research Institute
>>> 
>>> Director, High-Throughput Crystallization Screening Center
>>> 
>>> Research Associate Professor, Department of Biochemistry, University at
>>> Buffalo
>>> 
>>> 
>>> 
>>> Research Webpage <https://hwi.buffalo.edu/scientist-directory/sbowman/>
>>> 
>>> www.getacrystal.org<http://www.getacrystal.org>
>>> 
>>> 
>>> 
>>> sbow...@hwi.buffalo.edu
>>> 716-898-8623
>>> 
>>> 
>>> 
>>> 
>>> 
>>> *From: *CCP4 bulletin board  on behalf of Bernhard
>>> Rupp 
&

Re: [ccp4bb] challenges in structural biology

[Keller, Jacob]

What about developing a theory of how crystallization happens, i.e., what does 
the microscopic “picture” look like when crystals are forming, then predicting 
based on that picture? I remember looking into these things about ten years 
ago, and there were some cool things being done with various scattering methods 
and with AFM, but am not sure now what is the state of that art.

It would seem to me that crystallization is the search for intermolecular 
docking sites of sufficiently good (albeit presumably weak) affinity and 
consistent with the formation of a 3D lattice. I wonder what the affinity of 
these sites is, actually—I guess somewhere in the micromolar range, based on 
usual protein concentrations under crystallization conditions (10 mg/ml of a 40 
kD protein is 250 uM).

Presumably the various docking sites would change affinity based on the 
crystallization conditions, which would explain why some crystallization 
conditions work, others don’t?

Maybe a systematic look at all crystallization contacts in the PDB might yield 
some insight into crystallization? Maybe it’s already been done?

JPK



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Re: [ccp4bb] [EXTERNAL] Re: [ccp4bb] challenges in structural biology

[Reza Khayat]

Biophysical techniques used to screen samples (e.g. SEC, SEC-MALS, DLS, SAXS, 
CD...) before freezing are not as promising as many hope for. There are lots of 
examples where samples behave beautiful by multiple biophysics methods and then 
crash and burn on a cryo-EM grid. Consequently, screening freezing conditions 
become the bottle neck of cryo-EM.

?
Reza Khayat, PhD
Assistant Professor
City College of New York
Department of Chemistry
New York, NY 10031

From: CCP4 bulletin board  on behalf of Patrick Shaw 
Stewart 
Sent: Tuesday, July 23, 2019 1:35 PM
To: CCP4BB@JISCMAIL.AC.UK
Subject: [EXTERNAL] Re: [ccp4bb] challenges in structural biology



On a completely different tack, isn't the most pressing requirement in current 
structural biology a really good method of characterizing macromolecular 
samples before they are put onto cryoEM grids - ie analysing and screening them 
in solution.

For one thing I'm told those huge microscopes are quite prone to breaking down, 
which makes the queues (lines) to get onto them even longer.

That method might be (micro-scale) DLS - or something completely different.

Thx, Patrick


On Mon, Jul 15, 2019 at 8:44 PM Holton, James M 
<270165b9f4cf-dmarc-requ...@jiscmail.ac.uk<mailto:270165b9f4cf-dmarc-requ...@jiscmail.ac.uk>>
 wrote:
Hello folks,

I have the distinct honor of chairing the next Gordon Research
Conference on Diffraction Methods in Structural Biology (July 26-31
2020).  This meeting will focus on the biggest challenges currently
faced by structural biologists, and I mean actual real-world
challenges.  As much as possible, these challenges will take the form of
friendly competitions with defined parameters, data, a scoring system,
and "winners", to be established along with other unpublished results
only at the meeting, as is tradition at GRCs.

But what are the principle challenges in biological structure
determination today?  I of course have my own ideas, but I feel like I'm
forgetting something.  Obvious choices are:
1) getting crystals to diffract better
2) building models into low-resolution maps (after failing at #1)
3) telling if a ligand is really there or not
4) the phase problem (dealing with weak signal, twinning and
pseudotranslation)
5) what does "resolution" really mean?
6) why are macromolecular R factors so much higher than small-molecule ones?
7) what is the best way to process serial crystallography data?
8) how should one deal with non-isomorphism in multi-crystal methods?
9) what is the "structure" of something that won't sit still?

What am I missing?  Is industry facing different problems than
academics?  Are there specific challenges facing electron-based
techniques?  If so, could the combined strength of all the world's
methods developers solve them?  I'm interested in hearing the voice of
this community.  On or off-list is fine.

-James Holton
MAD Scientist




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--
 patr...@douglas.co.uk<mailto:patr...@douglas.co.uk>Douglas Instruments Ltd.
 Douglas House, East Garston, Hungerford, Berkshire, RG17 7HD, UK
 Directors: Peter Baldock, Patrick Shaw Stewart

 
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Re: [ccp4bb] challenges in structural biology

[Patrick Shaw Stewart]

On a completely different tack, isn’t the most pressing requirement in
current structural biology a really good method of characterizing
macromolecular samples *before *they are put onto cryoEM grids – ie
analysing *and screening them *in solution.

For one thing I’m told those huge microscopes are quite prone to breaking
down, which makes the queues (lines) to get onto them even longer.

That method might be (micro-scale) DLS – or something completely different.

Thx, Patrick


On Mon, Jul 15, 2019 at 8:44 PM Holton, James M <
270165b9f4cf-dmarc-requ...@jiscmail.ac.uk> wrote:

> Hello folks,
>
> I have the distinct honor of chairing the next Gordon Research
> Conference on Diffraction Methods in Structural Biology (July 26-31
> 2020).  This meeting will focus on the biggest challenges currently
> faced by structural biologists, and I mean actual real-world
> challenges.  As much as possible, these challenges will take the form of
> friendly competitions with defined parameters, data, a scoring system,
> and "winners", to be established along with other unpublished results
> only at the meeting, as is tradition at GRCs.
>
> But what are the principle challenges in biological structure
> determination today?  I of course have my own ideas, but I feel like I'm
> forgetting something.  Obvious choices are:
> 1) getting crystals to diffract better
> 2) building models into low-resolution maps (after failing at #1)
> 3) telling if a ligand is really there or not
> 4) the phase problem (dealing with weak signal, twinning and
> pseudotranslation)
> 5) what does "resolution" really mean?
> 6) why are macromolecular R factors so much higher than small-molecule
> ones?
> 7) what is the best way to process serial crystallography data?
> 8) how should one deal with non-isomorphism in multi-crystal methods?
> 9) what is the "structure" of something that won't sit still?
>
> What am I missing?  Is industry facing different problems than
> academics?  Are there specific challenges facing electron-based
> techniques?  If so, could the combined strength of all the world's
> methods developers solve them?  I'm interested in hearing the voice of
> this community.  On or off-list is fine.
>
> -James Holton
> MAD Scientist
>
>
> 
>
> To unsubscribe from the CCP4BB list, click the following link:
> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1
>


-- 
 patr...@douglas.co.ukDouglas Instruments Ltd.
 Douglas House, East Garston, Hungerford, Berkshire, RG17 7HD, UK
 Directors: Peter Baldock, Patrick Shaw Stewart

 http://www.douglas.co.uk
 Tel: 44 (0) 148-864-9090US toll-free 1-877-225-2034
 Regd. England 2177994, VAT Reg. GB 480 7371 36



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Re: [ccp4bb] challenges in structural biology

[Patrick Shaw Stewart]

Hi James – thx for starting a riveting thread.

(Of course) I agree with Dom, Janet, Artem and the cosmic cats that
crystallization is key.

I also agree with Artem a relatively modest investment in the fundamentals
of crystallization could make a big difference – even a 10% improvement in
productivity would save the community $ millions.

A high proportion of Nobel prizes (and highly-cited papers) are essentially
about method development.  So why is it so hard to get grants for new
scientific methods?  It’s as though current funding is only about charging
up the scientific motorways (interstates/autobahns for US/German citizens)
while ignoring the side-roads.  You have to claim that you will cure
cancer, diabetes, Ebola *and *ageing in less than six months for your grant
application to be considered.

But the side-roads have often yielded the most important scientific
breakthroughs.


The current approach to crystallization is (I’m told) a type of
"martingale" – that is, a betting scheme/stochastic process where your next
bet is based on analysis of previous rounds of betting.  The problem is
that if your starting assumptions are flawed it may take many decades to
arrive at a good solution.

What would fundamental research into crystallization look like?  I used to
think it was a matter of “boiling down” the dimensions in a typical
crystallization screen to say 10 “underlying variables” using multivariate
analysis.  Now I think this view is wrong.  There are a few variables that
are common to all crystallization experiments (temperature, pH and
“saturation” – whatever that is) but we also have to explore the space of
all the possible small molecules that can interact with - and probably bind
to - our target protein and help it to crystallize.  So crystallization
space is similar to chemical space – very big indeed.

I (now) think the targets of crystallization experiments are like this
picture:

*https://www.douglas.co.uk/f_ftp1/How%20desperate%20are%20you.jpg
*


There are some proteins that just need to be pushed out of solution to
crystallize – like lysozyme.

Then there are others that need to combine somehow with one particular
small molecule to make crystals.  For example, thaumatin crystallizes very
easily if there’s tartrate in the drop.

Others need two small molecule additives.  Presumably still others could
crystallize if only we could find the right combination of 3, 4 or 5 small
molecules.

(Tartrate in the example above is in a sense a “silver bullet”.  Hampton
Research called their screen that because they had the idea the additives
would self-select, so you could put lots of them in each condition.
Strangely, their Silver Bullet screen never worked as well as some of us
expected - I don’t know why.  But there isn’t one silver bullet – there
are, or could be, thousands.)

Random microseeding including cross-seeding works really well and is one of
Artem's silver bullets of crystallization methods – but we still have to
get our first crystals somehow.

Practical questions that could (and should!) be answered include:

1. Which are the best precipitants and how many do we need?  Maybe 4 or 5
would be enough.
2. How can we identify the best set of several hundred small molecules to
use as additives?
3. How many small molecules should we put in each crystallization trial?
4. What should we do about pH and temperature?


I think these questions could be answered by one lab, with good
experimental design and automation, using say 25 target proteins – not
including lysozyme, see above - that can be bought from Sigma etc (Artem,
making them yourself is too much like hard work!)

This can make both screening and optimization more efficient.  Yes it would
be a lot of work, but the current approach is a lot of work for hundreds
(thousands?) of labs all over the world - work that is largely wasted.

But it needs proper funding – and I don’t know how to get that.

Best wishes to all,

Patrick

Ps Of course I agree with Janet, Tom and others that good record-keeping is
essential.  But there is a limit to what we will learn if we insist on
solving structures at the same time.  I say just buy in the model proteins
by the gram and focus what is *really *going on in crystallization.


On Sun, Jul 21, 2019 at 4:29 PM Artem Evdokimov 
wrote:

> Excellent question :)
>
> First of all, thank you for putting this out to the community!
>
> Secondly, I agree with several of us who've written that a single
> conference is not enough to discuss all the possible topics.
>
> Thirdly, in my opinion all the other problems are secondary to the main
> (and only remaining!) problem in crystallography: getting
> diffraction-quality protein crystals reproducibly and quickly
>
> The amount of funding for serious crystallization research seems to be
> close to non-existent. In general methodology funding is hard to get, but
> crystallization seems to me like the 

Re: [ccp4bb] challenges in structural biology

[Engin Özkan]

On 7/23/19 3:35 AM, melanie.voll...@diamond.ac.uk wrote:
> No longer those 20 odd names for ammonium sulphate

You mean ammonium *sulfate*. As it is called across the pond. :)

On a related note on common nomenclature for recording crystallization 
experiments that Janet brought up:

I find it odd that we still do not report cryo-protection methods and 
conditions in PDB depositions. Given that a large fraction of the small 
molecules observed in crystal structures are derived from the 
cryo-protectants, one would think that reporting the contents of that 
solution (and pH) would be paramount to a PDB deposition. Surely, the 
crystallographic experiment has changed since 1990/use of synchrotron 
sources, which PDB has adjusted well to in most other aspects (e.g., 
including reporting of synchrotron x-ray optics and all the new 
detectors during submission).

Engin




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Re: [ccp4bb] challenges in structural biology

[melanie.voll...@diamond.ac.uk]

I don't think AI will do our job in future as it heavily relies on the crystal 
structures for training. However, as a community we should embrace this 
technology/method to help us solve our structures. And why not start with 
crystallisation? And again the PDB is in a good position here to enforce 
standards which will pave the way to make use of all the information in the 
database to train AI. All chemicals must be IUPAC conform an then the PDB can 
decide about trivial names based on a set of rules for humans (AI doesn't care 
how you name it as long as it is consistent). No longer those 20 odd names for 
ammonium sulphate as Janet pointed out years ago.


And regarding a magic bullet (as in one size fits all), why should a kinase 
crystallise in the same condition as a polymerase? They do different jobs in a 
different micro-environment within the cell so their chemical properties will 
be different. Perhaps there could be some common ground for evolutionary 
related molecules but a conserved active site doesn't mean a similar surface 
for crystal contacts which is the key bit in crystallisation, right?


But as Kay pointed out, crystallisation is a whole field on its own and will go 
beyond the GRC and the question asked by James.


M


From: CCP4 bulletin board  on behalf of Kay Diederichs 

Sent: 23 July 2019 08:59:10
To: ccp4bb
Subject: Re: [ccp4bb] challenges in structural biology

If you look at the nice figure at the top of the online article, do you believe 
that this (or rather, the correct) arrangement of domains/ molecules can be 
predicted from a couple of correlated mutations, and energy minimization? I 
think AI is a long way from that.  Finding the correct fold of a compact 
domain, yes I think it's getting there.

best,
Kay


On Tue, 23 Jul 2019 08:28:42 +0530, Nishant Varshney  wrote:

>What about AI doing our job in the future?
>
>https://www.nature.com/articles/d41586-019-01357-6?utm_source=Nature+Briefing_campaign=4c1d57fdf3-briefing-dy-20190722_medium=email_term=0_c9dfd39373-4c1d57fdf3-44201949
>
>Best Regards
>Nishant
>
>On Mon, 22 Jul 2019 at 11:30 PM, Sarah Bowman 
>wrote:
>
>> I'd like to point out that the MAchine Recognition of Crystallization
>> Outcomes (MARCO) makes a start to 'deep learning applied to crystallization
>> outcomes', at least in terms of being able to classify drop images
>> efficiently.
>>
>>
>>
>> There is obviously more work to be done to correlate these data with
>> crystallization cocktail components (which Janet and Tom point out the
>> difficulties with) and positive outcomes.  It seems the first step really
>> needs to be consistent descriptions and vocabulary - I fully agree with
>> Janet here!
>>
>>
>>
>> Reference on MARCO for those interested: Bruno AE, Charbonneau P, Newman
>> J, Snell EH, So DR, Vanhoucke V, et al. (2018) Classification of
>> crystallization outcomes using deep convolutional neural networks. PLoS ONE
>> 13(6): e0198883. https://doi.org/10.1371/journal.pone.0198883
>>
>>
>>
>> Cheers,
>>
>> Sarah
>>
>>
>>
>> *Sarah EJ Bowman, PhD*
>>
>>
>>
>> Associate Research Scientist, Hauptman-Woodward Medical Research Institute
>>
>> Director, High-Throughput Crystallization Screening Center
>>
>> Research Associate Professor, Department of Biochemistry, University at
>> Buffalo
>>
>>
>>
>> Research Webpage <https://hwi.buffalo.edu/scientist-directory/sbowman/>
>>
>> www.getacrystal.org<http://www.getacrystal.org>
>>
>>
>>
>> sbow...@hwi.buffalo.edu
>> 716-898-8623
>>
>>
>>
>>
>>
>> *From: *CCP4 bulletin board  on behalf of Bernhard
>> Rupp 
>> *Organization: *k.k. Hofkristallamt
>> *Reply-To: *"b...@hofkristallamt.org" 
>> *Date: *Monday, July 22, 2019 at 1:42 PM
>> *To: *"CCP4BB@JISCMAIL.AC.UK" 
>> *Subject: *Re: challenges in structural biology
>>
>>
>>
>> What about 'deep learning' applied to crystallization outcomes? Can it
>> guide individual trials better than intuition? Can it find previously
>> unknown promising combinations on a larger scale?
>>
>>
>>
>> I think several people were well aware of this need for some sort of sound
>> machine learning already 15 years ago but we had no cloud based AI
>>
>> services thenmaybe it is time to pick this up - particularly if face
>> recognition can classify the fine detail in faces maybe we finally could do
>> this with drop images as well...
>>
>>
>>
>> A summary of the state of affairs then is here:
>>
>>

Re: [ccp4bb] challenges in structural biology

[Kay Diederichs]

If you look at the nice figure at the top of the online article, do you believe 
that this (or rather, the correct) arrangement of domains/ molecules can be 
predicted from a couple of correlated mutations, and energy minimization? I 
think AI is a long way from that.  Finding the correct fold of a compact 
domain, yes I think it's getting there.

best,
Kay 


On Tue, 23 Jul 2019 08:28:42 +0530, Nishant Varshney  wrote:

>What about AI doing our job in the future?
>
>https://www.nature.com/articles/d41586-019-01357-6?utm_source=Nature+Briefing_campaign=4c1d57fdf3-briefing-dy-20190722_medium=email_term=0_c9dfd39373-4c1d57fdf3-44201949
>
>Best Regards
>Nishant
>
>On Mon, 22 Jul 2019 at 11:30 PM, Sarah Bowman 
>wrote:
>
>> I'd like to point out that the MAchine Recognition of Crystallization
>> Outcomes (MARCO) makes a start to 'deep learning applied to crystallization
>> outcomes', at least in terms of being able to classify drop images
>> efficiently.
>>
>>
>>
>> There is obviously more work to be done to correlate these data with
>> crystallization cocktail components (which Janet and Tom point out the
>> difficulties with) and positive outcomes.  It seems the first step really
>> needs to be consistent descriptions and vocabulary - I fully agree with
>> Janet here!
>>
>>
>>
>> Reference on MARCO for those interested: Bruno AE, Charbonneau P, Newman
>> J, Snell EH, So DR, Vanhoucke V, et al. (2018) Classification of
>> crystallization outcomes using deep convolutional neural networks. PLoS ONE
>> 13(6): e0198883. https://doi.org/10.1371/journal.pone.0198883
>>
>>
>>
>> Cheers,
>>
>> Sarah
>>
>>
>>
>> *Sarah EJ Bowman, PhD*
>>
>>
>>
>> Associate Research Scientist, Hauptman-Woodward Medical Research Institute
>>
>> Director, High-Throughput Crystallization Screening Center
>>
>> Research Associate Professor, Department of Biochemistry, University at
>> Buffalo
>>
>>
>>
>> Research Webpage 
>>
>> www.getacrystal.org
>>
>>
>>
>> sbow...@hwi.buffalo.edu
>> 716-898-8623
>>
>>
>>
>>
>>
>> *From: *CCP4 bulletin board  on behalf of Bernhard
>> Rupp 
>> *Organization: *k.k. Hofkristallamt
>> *Reply-To: *"b...@hofkristallamt.org" 
>> *Date: *Monday, July 22, 2019 at 1:42 PM
>> *To: *"CCP4BB@JISCMAIL.AC.UK" 
>> *Subject: *Re: challenges in structural biology
>>
>>
>>
>> What about 'deep learning' applied to crystallization outcomes? Can it
>> guide individual trials better than intuition? Can it find previously
>> unknown promising combinations on a larger scale?
>>
>>
>>
>> I think several people were well aware of this need for some sort of sound
>> machine learning already 15 years ago but we had no cloud based AI
>>
>> services thenmaybe it is time to pick this up - particularly if face
>> recognition can classify the fine detail in faces maybe we finally could do
>> this with drop images as well...
>>
>>
>>
>> A summary of the state of affairs then is here:
>>
>>
>> http://www.ruppweb.org/cvs/br/rupp_2004_methods_predictive_models_crystallization.pdf
>>
>>
>>
>> LG BR
>>
>>
>>
>>
>>
>> Am 21.07.19 um 23:04 schrieb Artem Evdokimov:
>>
>> Dear Kay
>>
>>
>>
>> I disagree that 'magic bullet' is impossible. I think the definition is
>> wrong here - magic bullet to me is a rational set of methods that (when
>> executed with precision and care) enable crystallization to the maximum
>> possible benefit. This includes everything - constructs, crystallization
>> design, etc. Part of the magic bullet is also a precise knowledge when
>> crystallization is unlikely (i.e. an actual proven predictor that
>> consistently discriminates between "you're going to succeed if you work
>> hard" and "it's doomed to fail, don't bother" scenarios in crystallization.
>>
>> The above is not sexy. It does not present itself as a lovely subject on
>> which to have international cocktail parties with politicians delivering
>> fancy speeches. But that is what is needed, and no one is funding that to
>> the best of my knowledge.
>>
>> What needs to be done is a significant amount of testing, standardization,
>> and methods development from the perspective of holistic outcome (i.e.
>> crystals that work) - and none of the previously advertised 'magic bullets'
>> work the way I just described.
>>
>> Having written this, I think you're right - this is a bit of a distraction
>> from James' original point. However it's a valid opportunity for a lively
>> discussion on its own :)
>>
>> Artem
>>
>> - Cosmic Cats approve of this message
>>
>> On Sun, Jul 21, 2019 at 4:52 PM Kay Diederichs <
>> kay.diederi...@uni-konstanz.de 
>> > wrote:
>>
>>  Dear Artem,
>>
>>  black or white is not my way of thinking, which is why I don't
>> believe in Hannibal's approach when it comes to crystallization.
>>
>>  None of the magic bullets that were advertised over the past decades
>> have proven generally applicable.  I believe more in incremental
>> 

Re: [ccp4bb] challenges in structural biology

[Nishant Varshney]

What about AI doing our job in the future?

https://www.nature.com/articles/d41586-019-01357-6?utm_source=Nature+Briefing_campaign=4c1d57fdf3-briefing-dy-20190722_medium=email_term=0_c9dfd39373-4c1d57fdf3-44201949

Best Regards
Nishant

On Mon, 22 Jul 2019 at 11:30 PM, Sarah Bowman 
wrote:

> I'd like to point out that the MAchine Recognition of Crystallization
> Outcomes (MARCO) makes a start to 'deep learning applied to crystallization
> outcomes', at least in terms of being able to classify drop images
> efficiently.
>
>
>
> There is obviously more work to be done to correlate these data with
> crystallization cocktail components (which Janet and Tom point out the
> difficulties with) and positive outcomes.  It seems the first step really
> needs to be consistent descriptions and vocabulary - I fully agree with
> Janet here!
>
>
>
> Reference on MARCO for those interested: Bruno AE, Charbonneau P, Newman
> J, Snell EH, So DR, Vanhoucke V, et al. (2018) Classification of
> crystallization outcomes using deep convolutional neural networks. PLoS ONE
> 13(6): e0198883. https://doi.org/10.1371/journal.pone.0198883
>
>
>
> Cheers,
>
> Sarah
>
>
>
> *Sarah EJ Bowman, PhD*
>
>
>
> Associate Research Scientist, Hauptman-Woodward Medical Research Institute
>
> Director, High-Throughput Crystallization Screening Center
>
> Research Associate Professor, Department of Biochemistry, University at
> Buffalo
>
>
>
> Research Webpage 
>
> www.getacrystal.org
>
>
>
> sbow...@hwi.buffalo.edu
> 716-898-8623
>
>
>
>
>
> *From: *CCP4 bulletin board  on behalf of Bernhard
> Rupp 
> *Organization: *k.k. Hofkristallamt
> *Reply-To: *"b...@hofkristallamt.org" 
> *Date: *Monday, July 22, 2019 at 1:42 PM
> *To: *"CCP4BB@JISCMAIL.AC.UK" 
> *Subject: *Re: challenges in structural biology
>
>
>
> What about 'deep learning' applied to crystallization outcomes? Can it
> guide individual trials better than intuition? Can it find previously
> unknown promising combinations on a larger scale?
>
>
>
> I think several people were well aware of this need for some sort of sound
> machine learning already 15 years ago but we had no cloud based AI
>
> services thenmaybe it is time to pick this up - particularly if face
> recognition can classify the fine detail in faces maybe we finally could do
> this with drop images as well...
>
>
>
> A summary of the state of affairs then is here:
>
>
> http://www.ruppweb.org/cvs/br/rupp_2004_methods_predictive_models_crystallization.pdf
>
>
>
> LG BR
>
>
>
>
>
> Am 21.07.19 um 23:04 schrieb Artem Evdokimov:
>
> Dear Kay
>
>
>
> I disagree that 'magic bullet' is impossible. I think the definition is
> wrong here - magic bullet to me is a rational set of methods that (when
> executed with precision and care) enable crystallization to the maximum
> possible benefit. This includes everything - constructs, crystallization
> design, etc. Part of the magic bullet is also a precise knowledge when
> crystallization is unlikely (i.e. an actual proven predictor that
> consistently discriminates between "you're going to succeed if you work
> hard" and "it's doomed to fail, don't bother" scenarios in crystallization.
>
> The above is not sexy. It does not present itself as a lovely subject on
> which to have international cocktail parties with politicians delivering
> fancy speeches. But that is what is needed, and no one is funding that to
> the best of my knowledge.
>
> What needs to be done is a significant amount of testing, standardization,
> and methods development from the perspective of holistic outcome (i.e.
> crystals that work) - and none of the previously advertised 'magic bullets'
> work the way I just described.
>
> Having written this, I think you're right - this is a bit of a distraction
> from James' original point. However it's a valid opportunity for a lively
> discussion on its own :)
>
> Artem
>
> - Cosmic Cats approve of this message
>
> On Sun, Jul 21, 2019 at 4:52 PM Kay Diederichs <
> kay.diederi...@uni-konstanz.de 
> > wrote:
>
>  Dear Artem,
>
>  black or white is not my way of thinking, which is why I don't
> believe in Hannibal's approach when it comes to crystallization.
>
>  None of the magic bullets that were advertised over the past decades
> have proven generally applicable.  I believe more in incremental
> improvement which in this case includes a few biophysical characterization
> methods, possibly improved microfluidics or other apparatus, and expanded
> screens. And a lot of hard work, perseverance, intuition, frustration
>
>   tolerance. Nothing that really needs huge funding - of course it
> does need money, but just a  share of what is anyway needed for the usual
> lab work including expression, purification, functional characterization,
> binding studies and the like.
>
>  One area where a huge amount of money was burnt is crystallization in
> space, on board of 

Re: [ccp4bb] challenges in structural biology

[Sarah Bowman]

I'd like to point out that the MAchine Recognition of Crystallization Outcomes 
(MARCO) makes a start to 'deep learning applied to crystallization outcomes', 
at least in terms of being able to classify drop images efficiently.

There is obviously more work to be done to correlate these data with 
crystallization cocktail components (which Janet and Tom point out the 
difficulties with) and positive outcomes.  It seems the first step really needs 
to be consistent descriptions and vocabulary - I fully agree with Janet here!

Reference on MARCO for those interested: Bruno AE, Charbonneau P, Newman J, 
Snell EH, So DR, Vanhoucke V, et al. (2018) Classification of crystallization 
outcomes using deep convolutional neural networks. PLoS ONE 13(6): e0198883. 
https://doi.org/10.1371/journal.pone.0198883

Cheers,
Sarah

Sarah EJ Bowman, PhD

Associate Research Scientist, Hauptman-Woodward Medical Research Institute
Director, High-Throughput Crystallization Screening Center
Research Associate Professor, Department of Biochemistry, University at Buffalo

Research Webpage
www.getacrystal.org

sbow...@hwi.buffalo.edu
716-898-8623


From: CCP4 bulletin board  on behalf of Bernhard Rupp 

Organization: k.k. Hofkristallamt
Reply-To: "b...@hofkristallamt.org" 
Date: Monday, July 22, 2019 at 1:42 PM
To: "CCP4BB@JISCMAIL.AC.UK" 
Subject: Re: challenges in structural biology

What about 'deep learning' applied to crystallization outcomes? Can it guide 
individual trials better than intuition? Can it find previously unknown 
promising combinations on a larger scale?

I think several people were well aware of this need for some sort of sound 
machine learning already 15 years ago but we had no cloud based AI
services thenmaybe it is time to pick this up - particularly if face 
recognition can classify the fine detail in faces maybe we finally could do 
this with drop images as well...

A summary of the state of affairs then is here:
http://www.ruppweb.org/cvs/br/rupp_2004_methods_predictive_models_crystallization.pdf

LG BR


Am 21.07.19 um 23:04 schrieb Artem Evdokimov:
Dear Kay

I disagree that 'magic bullet' is impossible. I think the definition is wrong 
here - magic bullet to me is a rational set of methods that (when executed with 
precision and care) enable crystallization to the maximum possible benefit. 
This includes everything - constructs, crystallization design, etc. Part of the 
magic bullet is also a precise knowledge when crystallization is unlikely (i.e. 
an actual proven predictor that consistently discriminates between "you're 
going to succeed if you work hard" and "it's doomed to fail, don't bother" 
scenarios in crystallization.
The above is not sexy. It does not present itself as a lovely subject on which 
to have international cocktail parties with politicians delivering fancy 
speeches. But that is what is needed, and no one is funding that to the best of 
my knowledge.
What needs to be done is a significant amount of testing, standardization, and 
methods development from the perspective of holistic outcome (i.e. crystals 
that work) - and none of the previously advertised 'magic bullets' work the way 
I just described.
Having written this, I think you're right - this is a bit of a distraction from 
James' original point. However it's a valid opportunity for a lively discussion 
on its own :)
Artem
- Cosmic Cats approve of this message
On Sun, Jul 21, 2019 at 4:52 PM Kay Diederichs 
mailto:kay.diederi...@uni-konstanz.de> 
>
 wrote:
 Dear Artem,
 black or white is not my way of thinking, which is why I don't believe in 
Hannibal's approach when it comes to crystallization.
 None of the magic bullets that were advertised over the past decades have 
proven generally applicable.  I believe more in incremental improvement which 
in this case includes a few biophysical characterization methods, possibly 
improved microfluidics or other apparatus, and expanded screens. And a lot of 
hard work, perseverance, intuition, frustration
  tolerance. Nothing that really needs huge funding - of course it does 
need money, but just a  share of what is anyway needed for the usual lab work 
including expression, purification, functional characterization, binding 
studies and the like.
 One area where a huge amount of money was burnt is crystallization in 
space, on board of e.g. the spacelab and ISS. This is for me an example of a 
mis-led approach to throw money at a difficult problem, with the expectation of 
a solution. Science does not work like that, and money in this case seems more 
to be the problem than the solution.
 This example may illustrate a certain failure of us scientists to resist 
the temptation to promise unrealistic outcomes when confronted with money 
provided for political 

Re: [ccp4bb] challenges in structural biology

[Bernhard Rupp]

> What about 'deep learning' applied to crystallization outcomes? Can it guide 
> individual trials better than intuition? Can it find previously unknown 
> promising combinations on a larger scale?

I think several people were well aware of this need for some sort of sound 
machine learning already 15 years ago but we had no cloud based AI
services thenmaybe it is time to pick this up - particularly if face 
recognition can classify the fine detail in faces maybe we finally could do 
this with drop images as well...

A summary of the state of affairs then is here:
http://www.ruppweb.org/cvs/br/rupp_2004_methods_predictive_models_crystallization.pdf

LG BR


Am 21.07.19 um 23:04 schrieb Artem Evdokimov:
> Dear Kay
>  
> 
> I disagree that 'magic bullet' is impossible. I think the definition is wrong 
> here - magic bullet to me is a rational set of methods that (when executed 
> with precision and care) enable crystallization to the maximum possible 
> benefit. This includes everything - constructs, crystallization design, etc. 
> Part of the magic bullet is also a precise knowledge when crystallization is 
> unlikely (i.e. an actual proven predictor that consistently discriminates 
> between "you're going to succeed if you work hard" and "it's doomed to fail, 
> don't bother" scenarios in crystallization.
> 
> The above is not sexy. It does not present itself as a lovely subject on 
> which to have international cocktail parties with politicians delivering 
> fancy speeches. But that is what is needed, and no one is funding that to the 
> best of my knowledge.
> 
> What needs to be done is a significant amount of testing, standardization, 
> and methods development from the perspective of holistic outcome (i.e. 
> crystals that work) - and none of the previously advertised 'magic bullets' 
> work the way I just described.
> 
> Having written this, I think you're right - this is a bit of a distraction 
> from James' original point. However it's a valid opportunity for a lively 
> discussion on its own :)
> 
> Artem
> 
> - Cosmic Cats approve of this message
> 
> 
> On Sun, Jul 21, 2019 at 4:52 PM Kay Diederichs 
> mailto:kay.diederi...@uni-konstanz.de>> 
> wrote:
> 
> Dear Artem,
> 
> black or white is not my way of thinking, which is why I don't believe in 
> Hannibal's approach when it comes to crystallization.
> 
> None of the magic bullets that were advertised over the past decades have 
> proven generally applicable.  I believe more in incremental improvement which 
> in this case includes a few biophysical characterization methods, possibly 
> improved microfluidics or other apparatus, and expanded screens. And a lot of 
> hard work, perseverance, intuition, frustration
>  tolerance. Nothing that really needs huge funding - of course it does 
> need money, but just a  share of what is anyway needed for the usual lab work 
> including expression, purification, functional characterization, binding 
> studies and the like.
> 
> One area where a huge amount of money was burnt is crystallization in 
> space, on board of e.g. the spacelab and ISS. This is for me an example of a 
> mis-led approach to throw money at a difficult problem, with the expectation 
> of a solution. Science does not work like that, and money in this case seems 
> more to be the problem than the solution.
> 
> This example may illustrate a certain failure of us scientists to resist 
> the temptation to promise unrealistic outcomes when confronted with money 
> provided for political reasons, which ultimately undermines our credibility. 
> But this takes us away from James' points.
> 
> best,
> 
> Kay
> 
> On Sun, 21 Jul 2019 16:06:48 -0400, Artem Evdokimov 
> mailto:artem.evdoki...@gmail.com>> wrote:
> 
> >Dear Kay,
> >
> >Even the small, badly diffracting and 'messed up' crystals are still
> >crystals. There is literally a phase transition (pun very much intended)
> >between growing *usable crystals* versus *having no crystals* (or having
> >crystals that do not qualify as 'diffraction quality' even under the most
> >favorable light). Points 2-9 fall into the 'I have crystals' bucket and
> >everything else is in the 'I have no crystals' bucket.
> >
> >I am being deliberately black and white of course.
> >
> >As to whether huge funding would help to bridge the 'phase gap' - to me
> >this is a purely theoretical question since to the best of my knowledge
> >there never was a 'huge funding' for this particular problem :) And if it
> >is true that the general belief in the art is that crystallization is not
> >worth investing into because there's no hope in it then of course it is a
> >self-fulfilling prophesy.
> >
> >There is an unresolved dichotomy buried in the sentiment above: it seems
> >that we (the community of structural biologists) more or less believe 
> that
> >crystallization research is not 

Re: [ccp4bb] challenges in structural biology

[Kay Diederichs]

Dear Artem, Tom, Janet,

for me and probably others the usage of words like 'magic bullet' (which you 
defend, or try to redefine) implies a belief-based esoteric approach that has 
little to do with science. I suggest that to obtain funding, 'magic bullets' 
should not be promised, because these cannot be delivered  (I gave the 
lo-gravity hi-funding example). 

That this discussion (including messages by Janet and Tom) happens at all 
suggests that crystallization is currently not a science - it lacks a 
consistent nomenclature and way of documentation, and suffers from strong 
publication bias (many unpublished negative results).

On the other hand, what you (Janet, Tom) write about the research that 
should/could be performed - this sounds a lot like a scientific approach, and 
is not different from what has been realized in other areas of crystallography. 
Yes, existing tools for predicting crystallization success are not consulted 
because the rate of false positives and false negatives is high. If those rates 
could be reproducibly reduced, I bet the usage would go up - that could start a 
feedback loop leading to even better predictions. Is work in this direction 
sexy? No. Is it useful? Yes. Is it hard work? Yes. Does it contribute to make 
crystallization a science? Yes.

What about 'deep learning' applied to crystallization outcomes? Can it guide 
individual trials better than intuition? Can it find previously unknown 
promising combinations on a larger scale?

Can this be funded? Yes of course. Your statement that crystallization gets no 
funding may be true in some countries (but aren't CCP4BB readers from the U.S. 
also reviewers?), but it's untrue in others - think of groups in France that 
obviously got long-term funding. And for space (low-gravity) - that amount of 
funding could have been used for a lot of meaningful earth-bound research.

Kay


Am 21.07.19 um 23:04 schrieb Artem Evdokimov:
> Dear Kay
>  
> 
> I disagree that 'magic bullet' is impossible. I think the definition is wrong 
> here - magic bullet to me is a rational set of methods that (when executed 
> with precision and care) enable crystallization to the maximum possible 
> benefit. This includes everything - constructs, crystallization design, etc. 
> Part of the magic bullet is also a precise knowledge when crystallization is 
> unlikely (i.e. an actual proven predictor that consistently discriminates 
> between "you're going to succeed if you work hard" and "it's doomed to fail, 
> don't bother" scenarios in crystallization.
> 
> The above is not sexy. It does not present itself as a lovely subject on 
> which to have international cocktail parties with politicians delivering 
> fancy speeches. But that is what is needed, and no one is funding that to the 
> best of my knowledge.
> 
> What needs to be done is a significant amount of testing, standardization, 
> and methods development from the perspective of holistic outcome (i.e. 
> crystals that work) - and none of the previously advertised 'magic bullets' 
> work the way I just described.
> 
> Having written this, I think you're right - this is a bit of a distraction 
> from James' original point. However it's a valid opportunity for a lively 
> discussion on its own :)
> 
> Artem
> 
> - Cosmic Cats approve of this message
> 
> 
> On Sun, Jul 21, 2019 at 4:52 PM Kay Diederichs 
> mailto:kay.diederi...@uni-konstanz.de>> 
> wrote:
> 
> Dear Artem,
> 
> black or white is not my way of thinking, which is why I don't believe in 
> Hannibal's approach when it comes to crystallization.
> 
> None of the magic bullets that were advertised over the past decades have 
> proven generally applicable.  I believe more in incremental improvement which 
> in this case includes a few biophysical characterization methods, possibly 
> improved microfluidics or other apparatus, and expanded screens. And a lot of 
> hard work, perseverance, intuition, frustration
>  tolerance. Nothing that really needs huge funding - of course it does 
> need money, but just a  share of what is anyway needed for the usual lab work 
> including expression, purification, functional characterization, binding 
> studies and the like.
> 
> One area where a huge amount of money was burnt is crystallization in 
> space, on board of e.g. the spacelab and ISS. This is for me an example of a 
> mis-led approach to throw money at a difficult problem, with the expectation 
> of a solution. Science does not work like that, and money in this case seems 
> more to be the problem than the solution.
> 
> This example may illustrate a certain failure of us scientists to resist 
> the temptation to promise unrealistic outcomes when confronted with money 
> provided for political reasons, which ultimately undermines our credibility. 
> But this takes us away from James' points.
> 
> best,
> 
> Kay
> 
> On Sun, 21 Jul 2019 16:06:48 -0400, Artem Evdokimov 
> 

Re: [ccp4bb] challenges in structural biology

[Peat, Tom (Manufacturing, Parkville)]

I will agree with Artem here-
Having knowledge as to whether crystallisation is likely or not with a given 
protein/ complex would be extremely useful.
If there were a set of screens/ tests/ experiments that one could run to show 
that it was 99% certain that something was not going to work (or conversely 
that something had a good chance of success) would be a goal and substantial 
step forward for the field.
Janet’s point is quite valid here- as we don’t know what people are doing (and 
we don’t have a defined vocabulary for describing experiments), we don’t 
actually know what has happened in the past, so it is hard to learn what should 
be done in the future.
So pulling together a defined way of describing what we do is likely the first 
step to understanding what has been done (and preserving it) so we know what to 
try in the future.

Cheers, tom

From: CCP4 bulletin board [mailto:CCP4BB@JISCMAIL.AC.UK] On Behalf Of Artem 
Evdokimov
Sent: Monday, 22 July 2019 7:04 AM
To: CCP4BB@JISCMAIL.AC.UK
Subject: Re: [ccp4bb] challenges in structural biology

Dear Kay


I disagree that 'magic bullet' is impossible. I think the definition is wrong 
here - magic bullet to me is a rational set of methods that (when executed with 
precision and care) enable crystallization to the maximum possible benefit. 
This includes everything - constructs, crystallization design, etc. Part of the 
magic bullet is also a precise knowledge when crystallization is unlikely (i.e. 
an actual proven predictor that consistently discriminates between "you're 
going to succeed if you work hard" and "it's doomed to fail, don't bother" 
scenarios in crystallization.

The above is not sexy. It does not present itself as a lovely subject on which 
to have international cocktail parties with politicians delivering fancy 
speeches. But that is what is needed, and no one is funding that to the best of 
my knowledge.

What needs to be done is a significant amount of testing, standardization, and 
methods development from the perspective of holistic outcome (i.e. crystals 
that work) - and none of the previously advertised 'magic bullets' work the way 
I just described.

Having written this, I think you're right - this is a bit of a distraction from 
James' original point. However it's a valid opportunity for a lively discussion 
on its own :)

Artem

- Cosmic Cats approve of this message


On Sun, Jul 21, 2019 at 4:52 PM Kay Diederichs 
mailto:kay.diederi...@uni-konstanz.de>> wrote:
Dear Artem,

black or white is not my way of thinking, which is why I don't believe in 
Hannibal's approach when it comes to crystallization.

None of the magic bullets that were advertised over the past decades have 
proven generally applicable.  I believe more in incremental improvement which 
in this case includes a few biophysical characterization methods, possibly 
improved microfluidics or other apparatus, and expanded screens. And a lot of 
hard work, perseverance, intuition, frustration
 tolerance. Nothing that really needs huge funding - of course it does need 
money, but just a  share of what is anyway needed for the usual lab work 
including expression, purification, functional characterization, binding 
studies and the like.

One area where a huge amount of money was burnt is crystallization in space, on 
board of e.g. the spacelab and ISS. This is for me an example of a mis-led 
approach to throw money at a difficult problem, with the expectation of a 
solution. Science does not work like that, and money in this case seems more to 
be the problem than the solution.

This example may illustrate a certain failure of us scientists to resist the 
temptation to promise unrealistic outcomes when confronted with money provided 
for political reasons, which ultimately undermines our credibility. But this 
takes us away from James' points.

best,

Kay

On Sun, 21 Jul 2019 16:06:48 -0400, Artem Evdokimov 
mailto:artem.evdoki...@gmail.com>> wrote:

>Dear Kay,
>
>Even the small, badly diffracting and 'messed up' crystals are still
>crystals. There is literally a phase transition (pun very much intended)
>between growing *usable crystals* versus *having no crystals* (or having
>crystals that do not qualify as 'diffraction quality' even under the most
>favorable light). Points 2-9 fall into the 'I have crystals' bucket and
>everything else is in the 'I have no crystals' bucket.
>
>I am being deliberately black and white of course.
>
>As to whether huge funding would help to bridge the 'phase gap' - to me
>this is a purely theoretical question since to the best of my knowledge
>there never was a 'huge funding' for this particular problem :) And if it
>is true that the general belief in the art is that crystallization is not
>worth investing into because there's no hope in it then of course it is a
>self-fulfilling prophesy.
>
>There is an unresolved dichotomy buried in the

Re: [ccp4bb] challenges in structural biology

[Artem Evdokimov]

Dear Kay


I disagree that 'magic bullet' is impossible. I think the definition is
wrong here - magic bullet to me is a rational set of methods that (when
executed with precision and care) enable crystallization to the maximum
possible benefit. This includes everything - constructs, crystallization
design, etc. Part of the magic bullet is also a precise knowledge when
crystallization is unlikely (i.e. an actual proven predictor that
consistently discriminates between "you're going to succeed if you work
hard" and "it's doomed to fail, don't bother" scenarios in crystallization.

The above is not sexy. It does not present itself as a lovely subject on
which to have international cocktail parties with politicians delivering
fancy speeches. But that is what is needed, and no one is funding that to
the best of my knowledge.

What needs to be done is a significant amount of testing, standardization,
and methods development from the perspective of holistic outcome (i.e.
crystals that work) - and none of the previously advertised 'magic bullets'
work the way I just described.

Having written this, I think you're right - this is a bit of a distraction
from James' original point. However it's a valid opportunity for a lively
discussion on its own :)

Artem

- Cosmic Cats approve of this message


On Sun, Jul 21, 2019 at 4:52 PM Kay Diederichs <
kay.diederi...@uni-konstanz.de> wrote:

> Dear Artem,
>
> black or white is not my way of thinking, which is why I don't believe in
> Hannibal's approach when it comes to crystallization.
>
> None of the magic bullets that were advertised over the past decades have
> proven generally applicable.  I believe more in incremental improvement
> which in this case includes a few biophysical characterization methods,
> possibly improved microfluidics or other apparatus, and expanded screens.
> And a lot of hard work, perseverance, intuition, frustration
>  tolerance. Nothing that really needs huge funding - of course it does
> need money, but just a  share of what is anyway needed for the usual lab
> work including expression, purification, functional characterization,
> binding studies and the like.
>
> One area where a huge amount of money was burnt is crystallization in
> space, on board of e.g. the spacelab and ISS. This is for me an example of
> a mis-led approach to throw money at a difficult problem, with the
> expectation of a solution. Science does not work like that, and money in
> this case seems more to be the problem than the solution.
>
> This example may illustrate a certain failure of us scientists to resist
> the temptation to promise unrealistic outcomes when confronted with money
> provided for political reasons, which ultimately undermines our
> credibility. But this takes us away from James' points.
>
> best,
>
> Kay
>
> On Sun, 21 Jul 2019 16:06:48 -0400, Artem Evdokimov <
> artem.evdoki...@gmail.com> wrote:
>
> >Dear Kay,
> >
> >Even the small, badly diffracting and 'messed up' crystals are still
> >crystals. There is literally a phase transition (pun very much intended)
> >between growing *usable crystals* versus *having no crystals* (or having
> >crystals that do not qualify as 'diffraction quality' even under the most
> >favorable light). Points 2-9 fall into the 'I have crystals' bucket and
> >everything else is in the 'I have no crystals' bucket.
> >
> >I am being deliberately black and white of course.
> >
> >As to whether huge funding would help to bridge the 'phase gap' - to me
> >this is a purely theoretical question since to the best of my knowledge
> >there never was a 'huge funding' for this particular problem :) And if it
> >is true that the general belief in the art is that crystallization is not
> >worth investing into because there's no hope in it then of course it is a
> >self-fulfilling prophesy.
> >
> >There is an unresolved dichotomy buried in the sentiment above: it seems
> >that we (the community of structural biologists) more or less believe that
> >crystallization research is not fundamentally fruitful (hence the
> >no-funding situation). However, anyone who undertakes significant efforts
> >to determine an actual structure using crystallography inevitably *has to*
> >crystallize their target of interest - and therefore by definition has
> hope
> >that their particular target will work out, against the overall gloomy
> >outlook on the crystallization science as a whole. So we either are a
> >collective of self-induced schizophrenics, or the general sentiment is
> >wrong and systematic crystallization research is meaningful and
> >fruitful - *just
> >very very hard*.
> >
> >In ~200 BC Hannibal reportedly said "I will find a way or make one". I
> >think that if we approach problem #1 with this attitude (and an equivalent
> >of a very large army's worth in funding) then it can be solved.
> >
> >Artem
> >
> >- Cosmic Cats approve of this message
> >
> >
> >On Sun, Jul 21, 2019 at 1:55 PM Kay Diederichs <
> >kay.diederi...@uni-konstanz.de> 

Re: [ccp4bb] challenges in structural biology

[Artem Evdokimov]

Dear Kay,

Even the small, badly diffracting and 'messed up' crystals are still
crystals. There is literally a phase transition (pun very much intended)
between growing *usable crystals* versus *having no crystals* (or having
crystals that do not qualify as 'diffraction quality' even under the most
favorable light). Points 2-9 fall into the 'I have crystals' bucket and
everything else is in the 'I have no crystals' bucket.

I am being deliberately black and white of course.

As to whether huge funding would help to bridge the 'phase gap' - to me
this is a purely theoretical question since to the best of my knowledge
there never was a 'huge funding' for this particular problem :) And if it
is true that the general belief in the art is that crystallization is not
worth investing into because there's no hope in it then of course it is a
self-fulfilling prophesy.

There is an unresolved dichotomy buried in the sentiment above: it seems
that we (the community of structural biologists) more or less believe that
crystallization research is not fundamentally fruitful (hence the
no-funding situation). However, anyone who undertakes significant efforts
to determine an actual structure using crystallography inevitably *has to*
crystallize their target of interest - and therefore by definition has hope
that their particular target will work out, against the overall gloomy
outlook on the crystallization science as a whole. So we either are a
collective of self-induced schizophrenics, or the general sentiment is
wrong and systematic crystallization research is meaningful and
fruitful - *just
very very hard*.

In ~200 BC Hannibal reportedly said "I will find a way or make one". I
think that if we approach problem #1 with this attitude (and an equivalent
of a very large army's worth in funding) then it can be solved.

Artem

- Cosmic Cats approve of this message


On Sun, Jul 21, 2019 at 1:55 PM Kay Diederichs <
kay.diederi...@uni-konstanz.de> wrote:

> Hi Artem,
>
> you are certainly correct in that James' points 2-9 would be moot if his
> point 1 were solved. But as long as this is not the case, we resort to work
> with few and/or small and/or badly diffracting and/or non-isomorphous
> crystals, which makes points 2-9 very relevant.
>
> Maybe the reason why crystallization research is not well funded is that
> it is not expected to yield significant improvements. Personally, I think
> that even huge funding would not result in methods that succeed in
> crystallizing all molecules.
>
> best,
> Kay
>
> On Sun, 21 Jul 2019 11:28:14 -0400, Artem Evdokimov <
> artem.evdoki...@gmail.com> wrote:
>
> >Excellent question :)
> >
> >First of all, thank you for putting this out to the community!
> >
> >Secondly, I agree with several of us who've written that a single
> >conference is not enough to discuss all the possible topics.
> >
> >Thirdly, in my opinion all the other problems are secondary to the main
> >(and only remaining!) problem in crystallography: getting
> >diffraction-quality protein crystals reproducibly and quickly
> >
> >The amount of funding for serious crystallization research seems to be
> >close to non-existent. In general methodology funding is hard to get, but
> >crystallization seems to me like the absolute underdog of the method pool
> -
> >the true 'red headed stepchild' of the methods development funders.
> >
> >At risk of repeating myself - the other problems (worthy, significant, and
> >urgent as they are!) are subservient to the main issue at hand - namely
> >that crystallization remains an unpredictable and artful phenomenon while
> >literally all other aspects of structure determination process (the gene
> to
> >structure pipeline, whatever you might call it)have made astronomic leaps
> >forward.
> >
> >Artem
> >- Cosmic Cats approve of this message
> >
> >
> >On Mon, Jul 15, 2019 at 3:44 PM Holton, James M <
> >270165b9f4cf-dmarc-requ...@jiscmail.ac.uk> wrote:
> >
> >> Hello folks,
> >>
> >> I have the distinct honor of chairing the next Gordon Research
> >> Conference on Diffraction Methods in Structural Biology (July 26-31
> >> 2020).  This meeting will focus on the biggest challenges currently
> >> faced by structural biologists, and I mean actual real-world
> >> challenges.  As much as possible, these challenges will take the form of
> >> friendly competitions with defined parameters, data, a scoring system,
> >> and "winners", to be established along with other unpublished results
> >> only at the meeting, as is tradition at GRCs.
> >>
> >> But what are the principle challenges in biological structure
> >> determination today?  I of course have my own ideas, but I feel like I'm
> >> forgetting something.  Obvious choices are:
> >> 1) getting crystals to diffract better
> >> 2) building models into low-resolution maps (after failing at #1)
> >> 3) telling if a ligand is really there or not
> >> 4) the phase problem (dealing with weak signal, twinning and
> >> pseudotranslation)
> >> 5) what 

Re: [ccp4bb] challenges in structural biology

[Phoebe A. Rice]

Hi All,
  Agreed! 
  Crystallization methods have improved in some ways, but at least in my 
experience the real energy barrier is usually knowing enough about the quirky 
biochemistry of the particular idiosyncratic complex we happen to be working 
on.  That means that one may need a grant's worth of biochemical plans anyway, 
whether or not "determine structure" is included as an aim (which of course 
won't get funded unless diffracting crystals are in hand, which is probably an 
issue for another day ...).  Some of the "magic bullets" of the past have 
turned out to rely on assumptions that remind one of spherical cow jokes.  Or 
to require a very large up-front investment in finicky microfluidics or other 
technologies that just isn't practical for small labs that try to do 
biochemistry as well as structure. 
  A long-term worry of mine is training of the next generation:  it is quite 
possible to solve structures now just by pushing buttons in software such as 
phenix now, and in many cases those suites do make the best decisions, but they 
deprive learners of understanding what is going on inside the black box.  Often 
I just can't find the relevant tables of statistics, etc to explain to a 
student why an autosol run produced an ugly map - e.g. cross R factor vs. 
resolution for native vs. alleged derivative?  FOM vs. resolution?  Clearly 
labeled statistics before and after whatever density modification happened?  
Even a clear, concise log of what kind(s) of density modification were applied? 
 I get frustrated when other people's students can't tell me exactly what 
they've already tried, but it isn't always their fault.
  Best,
 Phoebe

  ~~~
Phoebe A. Rice
Dept. of Biochem & Mol. Biol. and
  Committee on Microbiology
https://voices.uchicago.edu/phoebericelab/

On 7/21/19, 12:55 PM, "CCP4 bulletin board on behalf of Kay Diederichs" 
 wrote:

Hi Artem,

you are certainly correct in that James' points 2-9 would be moot if his 
point 1 were solved. But as long as this is not the case, we resort to work 
with few and/or small and/or badly diffracting and/or non-isomorphous crystals, 
which makes points 2-9 very relevant. 

Maybe the reason why crystallization research is not well funded is that it 
is not expected to yield significant improvements. Personally, I think that 
even huge funding would not result in methods that succeed in crystallizing all 
molecules.

best,
Kay

On Sun, 21 Jul 2019 11:28:14 -0400, Artem Evdokimov 
 wrote:

>Excellent question :)
>
>First of all, thank you for putting this out to the community!
>
>Secondly, I agree with several of us who've written that a single
>conference is not enough to discuss all the possible topics.
>
>Thirdly, in my opinion all the other problems are secondary to the main
>(and only remaining!) problem in crystallography: getting
>diffraction-quality protein crystals reproducibly and quickly
>
>The amount of funding for serious crystallization research seems to be
>close to non-existent. In general methodology funding is hard to get, but
>crystallization seems to me like the absolute underdog of the method pool -
>the true 'red headed stepchild' of the methods development funders.
>
>At risk of repeating myself - the other problems (worthy, significant, and
>urgent as they are!) are subservient to the main issue at hand - namely
>that crystallization remains an unpredictable and artful phenomenon while
>literally all other aspects of structure determination process (the gene to
>structure pipeline, whatever you might call it)have made astronomic leaps
>forward.
>
>Artem
>- Cosmic Cats approve of this message
>
>
>On Mon, Jul 15, 2019 at 3:44 PM Holton, James M <
>270165b9f4cf-dmarc-requ...@jiscmail.ac.uk> wrote:
>
>> Hello folks,
>>
>> I have the distinct honor of chairing the next Gordon Research
>> Conference on Diffraction Methods in Structural Biology (July 26-31
>> 2020).  This meeting will focus on the biggest challenges currently
>> faced by structural biologists, and I mean actual real-world
>> challenges.  As much as possible, these challenges will take the form of
>> friendly competitions with defined parameters, data, a scoring system,
>> and "winners", to be established along with other unpublished results
>> only at the meeting, as is tradition at GRCs.
>>
>> But what are the principle challenges in biological structure
>> determination today?  I of course have my own ideas, but I feel like I'm
>> forgetting something.  Obvious choices are:
>> 1) getting crystals to diffract better
>> 2) building models into low-resolution maps (after failing at #1)
>> 3) telling if a ligand is really there or not
>> 4) the phase problem (dealing with weak signal, twinning and
>> 

Re: [ccp4bb] challenges in structural biology

[Kay Diederichs]

Hi Artem,

you are certainly correct in that James' points 2-9 would be moot if his point 
1 were solved. But as long as this is not the case, we resort to work with few 
and/or small and/or badly diffracting and/or non-isomorphous crystals, which 
makes points 2-9 very relevant. 

Maybe the reason why crystallization research is not well funded is that it is 
not expected to yield significant improvements. Personally, I think that even 
huge funding would not result in methods that succeed in crystallizing all 
molecules.

best,
Kay

On Sun, 21 Jul 2019 11:28:14 -0400, Artem Evdokimov  
wrote:

>Excellent question :)
>
>First of all, thank you for putting this out to the community!
>
>Secondly, I agree with several of us who've written that a single
>conference is not enough to discuss all the possible topics.
>
>Thirdly, in my opinion all the other problems are secondary to the main
>(and only remaining!) problem in crystallography: getting
>diffraction-quality protein crystals reproducibly and quickly
>
>The amount of funding for serious crystallization research seems to be
>close to non-existent. In general methodology funding is hard to get, but
>crystallization seems to me like the absolute underdog of the method pool -
>the true 'red headed stepchild' of the methods development funders.
>
>At risk of repeating myself - the other problems (worthy, significant, and
>urgent as they are!) are subservient to the main issue at hand - namely
>that crystallization remains an unpredictable and artful phenomenon while
>literally all other aspects of structure determination process (the gene to
>structure pipeline, whatever you might call it)have made astronomic leaps
>forward.
>
>Artem
>- Cosmic Cats approve of this message
>
>
>On Mon, Jul 15, 2019 at 3:44 PM Holton, James M <
>270165b9f4cf-dmarc-requ...@jiscmail.ac.uk> wrote:
>
>> Hello folks,
>>
>> I have the distinct honor of chairing the next Gordon Research
>> Conference on Diffraction Methods in Structural Biology (July 26-31
>> 2020).  This meeting will focus on the biggest challenges currently
>> faced by structural biologists, and I mean actual real-world
>> challenges.  As much as possible, these challenges will take the form of
>> friendly competitions with defined parameters, data, a scoring system,
>> and "winners", to be established along with other unpublished results
>> only at the meeting, as is tradition at GRCs.
>>
>> But what are the principle challenges in biological structure
>> determination today?  I of course have my own ideas, but I feel like I'm
>> forgetting something.  Obvious choices are:
>> 1) getting crystals to diffract better
>> 2) building models into low-resolution maps (after failing at #1)
>> 3) telling if a ligand is really there or not
>> 4) the phase problem (dealing with weak signal, twinning and
>> pseudotranslation)
>> 5) what does "resolution" really mean?
>> 6) why are macromolecular R factors so much higher than small-molecule
>> ones?
>> 7) what is the best way to process serial crystallography data?
>> 8) how should one deal with non-isomorphism in multi-crystal methods?
>> 9) what is the "structure" of something that won't sit still?
>>
>> What am I missing?  Is industry facing different problems than
>> academics?  Are there specific challenges facing electron-based
>> techniques?  If so, could the combined strength of all the world's
>> methods developers solve them?  I'm interested in hearing the voice of
>> this community.  On or off-list is fine.
>>
>> -James Holton
>> MAD Scientist
>>
>>
>> 
>>
>> To unsubscribe from the CCP4BB list, click the following link:
>> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1
>>
>
>
>
>To unsubscribe from the CCP4BB list, click the following link:
>https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1
>



To unsubscribe from the CCP4BB list, click the following link:
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Re: [ccp4bb] challenges in structural biology

[Manoj Saxena]

Dear all,
First of all, I would like to thanks James for this initiative and sparking
this discussion in the community. There were many valid points raised by
different people about the limitations of the current approaches in
crystallization, interpretation of the structural data and the definition
of terms involved like resolution, serial crystallography, and the
relevance/reliability of the "structural information" in terms of its
biological significance as gleaned from the crystal structures.
One another point that was frequently highlighted in the thread by many
that somehow an integrated approach using techniques like cryo-EM,
spectroscopy and NMR could help overcome some of the limitations in the
better understanding structures for understanding the functions of
biological molecules.



@James  My suggestion is that It would be a great service to all the
community if suggestions and the points (even if they are divergent
viewpoints) that comes out of this initiative could be published somewhere.
In case you have already planning to do it, many thanks in advance.

P.S. These type of discussions should also be part of other meetings and
training schools like CCP4, CSHL, and Rapidata-



Regards
Manoj Saxena





El mié., 17 jul. 2019 a las 15:54, Edward Snell ()
escribió:

> /Lurk mode off
>
> Not to steal any of the thunder from James, but I would also point out
> that those interested in the discussion are the perfect attendees for the
> Gordon Research Conference next year - July 26th to 31st with a Gordon
> Research Seminar for your students and postdocs - July 25th-26th - save the
> date and consider attending. In my opinion, this is one of the best
> meetings in this subject area.
>
> Also, from past experience, it would be really great if any vendors or
> other organizations seeing this chain of emails would consider putting the
> Conference or Seminar on their list for support in 2020. It really helps
> bring in great speakers, start many new collaborations, and grow the field.
>
> Best,
>
> Eddie
>
> /Lurk mode on
>
> Edward Snell Ph.D.
>
> Biological Small Angle Scattering Theory and Practice, Eaton E. Lattman,
> Thomas D. Grant, and Edward H. Snell.
> Available through all good bookshops, or direct from Oxford University
> Press
>
> Director of the NSF BioXFEL Science and Technology Center
> President and CEO Hauptman-Woodward Medical Research Institute
> BioInnovations Chaired Professorship, University at Buffalo, SUNY
> 700 Ellicott Street, Buffalo, NY 14203-1102
> hwi.buffalo.edu
> Phone:   (716) 898 8631 Fax: (716) 898 8660
> Skype:eddie.snell Email: esn...@hwi.buffalo.edu
> Webpage: https://hwi.buffalo.edu/scientist-directory/snell/
>
> Heisenberg was probably here!
>
>
> -Original Message-
> From: CCP4 bulletin board [mailto:CCP4BB@JISCMAIL.AC.UK] On Behalf Of
> Holton, James M
> Sent: Monday, July 15, 2019 3:44 PM
> To: CCP4BB@JISCMAIL.AC.UK
> Subject: [ccp4bb] challenges in structural biology
>
> Hello folks,
>
> I have the distinct honor of chairing the next Gordon Research Conference
> on Diffraction Methods in Structural Biology (July 26-31 2020).  This
> meeting will focus on the biggest challenges currently faced by structural
> biologists, and I mean actual real-world challenges.  As much as possible,
> these challenges will take the form of friendly competitions with defined
> parameters, data, a scoring system, and "winners", to be established along
> with other unpublished results only at the meeting, as is tradition at GRCs.
>
> But what are the principle challenges in biological structure
> determination today?  I of course have my own ideas, but I feel like I'm
> forgetting something.  Obvious choices are:
> 1) getting crystals to diffract better
> 2) building models into low-resolution maps (after failing at #1)
> 3) telling if a ligand is really there or not
> 4) the phase problem (dealing with weak signal, twinning and
> pseudotranslation)
> 5) what does "resolution" really mean?
> 6) why are macromolecular R factors so much higher than small-molecule
> ones?
> 7) what is the best way to process serial crystallography data?
> 8) how should one deal with non-isomorphism in multi-crystal methods?
> 9) what is the "structure" of something that won't sit still?
>
> What am I missing?  Is industry facing different problems than academics?
> Are there specific challenges facing electron-based techniques?  If so,
> could the combined strength of all the world's methods developers solve
> them?  I'm interested in hearing the voice of this community.  On or
> off-list is fine.
>
> -James Holton
> MAD Scientist
>
>
> 

Re: [ccp4bb] challenges in structural biology

[Edward Snell]

/Lurk mode off

Not to steal any of the thunder from James, but I would also point out that 
those interested in the discussion are the perfect attendees for the Gordon 
Research Conference next year - July 26th to 31st with a Gordon Research 
Seminar for your students and postdocs - July 25th-26th - save the date and 
consider attending. In my opinion, this is one of the best meetings in this 
subject area.

Also, from past experience, it would be really great if any vendors or other 
organizations seeing this chain of emails would consider putting the Conference 
or Seminar on their list for support in 2020. It really helps bring in great 
speakers, start many new collaborations, and grow the field.

Best,

Eddie

/Lurk mode on

Edward Snell Ph.D.

Biological Small Angle Scattering Theory and Practice, Eaton E. Lattman, Thomas 
D. Grant, and Edward H. Snell. 
Available through all good bookshops, or direct from Oxford University Press  

Director of the NSF BioXFEL Science and Technology Center
President and CEO Hauptman-Woodward Medical Research Institute
BioInnovations Chaired Professorship, University at Buffalo, SUNY
700 Ellicott Street, Buffalo, NY 14203-1102
hwi.buffalo.edu
Phone:   (716) 898 8631 Fax: (716) 898 8660 
Skype:eddie.snell Email: esn...@hwi.buffalo.edu  
Webpage: https://hwi.buffalo.edu/scientist-directory/snell/

Heisenberg was probably here!


-Original Message-
From: CCP4 bulletin board [mailto:CCP4BB@JISCMAIL.AC.UK] On Behalf Of Holton, 
James M
Sent: Monday, July 15, 2019 3:44 PM
To: CCP4BB@JISCMAIL.AC.UK
Subject: [ccp4bb] challenges in structural biology

Hello folks,

I have the distinct honor of chairing the next Gordon Research Conference on 
Diffraction Methods in Structural Biology (July 26-31 2020).  This meeting will 
focus on the biggest challenges currently faced by structural biologists, and I 
mean actual real-world challenges.  As much as possible, these challenges will 
take the form of friendly competitions with defined parameters, data, a scoring 
system, and "winners", to be established along with other unpublished results 
only at the meeting, as is tradition at GRCs.

But what are the principle challenges in biological structure determination 
today?  I of course have my own ideas, but I feel like I'm forgetting 
something.  Obvious choices are:
1) getting crystals to diffract better
2) building models into low-resolution maps (after failing at #1)
3) telling if a ligand is really there or not
4) the phase problem (dealing with weak signal, twinning and
pseudotranslation)
5) what does "resolution" really mean?
6) why are macromolecular R factors so much higher than small-molecule ones?
7) what is the best way to process serial crystallography data?
8) how should one deal with non-isomorphism in multi-crystal methods?
9) what is the "structure" of something that won't sit still?

What am I missing?  Is industry facing different problems than academics?  Are 
there specific challenges facing electron-based techniques?  If so, could the 
combined strength of all the world's methods developers solve them?  I'm 
interested in hearing the voice of this community.  On or off-list is fine.

-James Holton
MAD Scientist




To unsubscribe from the CCP4BB list, click the following link:
https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1



To unsubscribe from the CCP4BB list, click the following link:
https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1

Re: [ccp4bb] challenges in structural biology

[colin.n...@diamond.ac.uk]

Hi James, Tristan and ccp4
If the meeting is diffraction methods in structural biology then there would be 
plenty to discuss. My points are probably more relevant to other methods but 
cover areas raised in the discussion.

1. Electron cryo-tomography. My understanding is that if you are trying to 
image protein molecules within cells one can collect more particles even though 
the cells themselves are different. In principle, the signal from each protein 
molecule is not affected by the surrounding material as each element adds 
coherently. For tomography one  fractionates the dose (Hoppe, W. & Hegerl, R. 
(1981). Ultramicroscopy. 6, 205-206)  to get some 3D information. The signal 
from each protein for the same dose should be the same as for more normal 
single particle em. If one is interested in membrane protein the problem of 
alignment is reduced somewhat as 2 of the orientation parameters are at least 
partly determined. Admittedly one has to identify the protein. This is easier 
for larger proteins as shown by the work on the nuclear pore complex. My view 
is that these techniques will progress with time to smaller protein molecules 
once the technical challenges are overcome. 

2. The complementary nature of electron microscopy and crystallography 
regarding floppy domains is a good point. For disorder on a scale less than a 
full domain the issue is what is realistic and representative. The crystal 
environment can force sidechains, loops, chain termini  to have a particular 
position. I seem to remember James showing various structures of the same 
protein (lysozyme?) linked together to give a rather nice molecular dynamics 
type movie. The implication is that each structure selects one of the 
conformations which naturally occur in solution and one could use the movie to 
compare with molecular dynamics , though judging which of these is most 
realistic is another matter.

Cheers
 Colin


-Original Message-
From: CCP4 bulletin board  On Behalf Of Tristan Croll
Sent: 17 July 2019 09:19
To: ccp4bb 
Subject: Re: [ccp4bb] challenges in structural biology

Hi Radu,

Barring some truly spectacular advances, I think that crystallography is going 
to have a major role to play for a long time yet. Looking at single-particle 
cryoEM, for almost every target apart from the few ultra-rigid "rocks" the 
reconstruction will have a wide range of resolutions from (near)atomic in the 
rigid core to fuzzy blobs out on the floppy exterior. Yes, modern focused 
reconstruction techniques are improving upon this all the time, but there will 
be limits - and the problem is much more serious when it comes to electron 
cryo-tomography methods where you can't simply collect more particles! I think 
there's some lovely potential complementarity between cryo-EM and 
crystallography here: almost by definition, these peripheral mobile domains 
tend to be things that fold independently of the main body of the complex - so 
why not express them independently and see if they crystallise? That way you 
get the best of both worlds: the initial cryo-EM reconstruction allows some 
informed decision making on what
construct(s) is/are likely to reliably crystallise, crystallisation of those 
domains gives you the atomic-resolution description you need, and modelling 
these back into the cryo-EM map allows you to study them in a more natural 
context.

To bring things back to the original topic, I guess that's what I'd like to see 
more of: rather than seeing the methods as in fundamental competition, where 
are the *complementarities* between crystallography and newer techniques?

Best regards,

Tristan

On 2019-07-17 08:43, r...@mrc-lmb.cam.ac.uk wrote:
> Hi Both,
> 
> I am not questioning the PDB stats, the issue was whether (crystal) 
> structures are sufficiently relevant to address biological questions 
> and justify the resources. Fragment screening is one example where 
> investment in protein crystallography can still be justified (for 
> now). But it doesn't really ask or answer biological questions... for 
> these, whether we like it or not, macromolecular crystallography (or 
> NMR, even in cell) cannot be the future. In my opinion :-)
> 
> Best wishes,
> 
> Radu
> 
> 
>> Stating the crystallography is dead might be a bit premature, it is 
>> still king for depositions.
>> 
>> 
>> 
>> In 2017 we had a large number of fragment screening experiments 
>> deposited.
>> 
>> 
>> 
>> 
>> 
>> 
>> 
>> From: CCP4 bulletin board  On Behalf Of Nukri 
>> Sanishvili
>> Sent: 15 July 2019 23:09
>> To: CCP4BB@JISCMAIL.AC.UK
>> Subject: Re: [ccp4bb] challenges in structural biology
>> 
>> 
>> 
>> I know it is going to hijack the original topic but I could not 
>> help...
>> 
>> 
>> 
>> “The reports of d

Re: [ccp4bb] challenges in structural biology

[Robbie Joosten]

Hi James,

Related to Joel's post, how does on interpret the wealth of structural data we 
already have comprehensively. If you have 30 structures of the same protein in 
slightly different states, how do you inspect the differences?

Cheers,
Roobie

On 17 Jul 2019 13:44, Joel Sussman  wrote:
Dear James
Another key point, which is directly related to the discussion of 'why' one 
does a particular structural study, is:
how one explains the results to others, including even to 'non structural 
biologists’.
This is important and INDEPENDENT of the particular experimental procedure. 
Some examples of possible ways to this can be seen in Proteopedia,
e.g.
* Insulin  - http://proteopedia.org/w/Insulin
* Tutorial:How do we get the oxygen we breathe - 
http://proteopedia.org/w/Tutorial:How_do_we_get_the_oxygen_we_breathe
* Immunodeficiency virus protease - 
http://proteopedia.org/w/Immunodeficiency_virus_protease
* An Interactive 3D Complement to a 'Molecular Cell' paper - 
http://proteopedia.org/w/Journal:Molecular_Cell:1

Joel


Prof. Joel L. Sussman  
joel.suss...@weizmann.ac.il<mailto:joel.suss...@weizmann.ac.il>   
www.weizmann.ac.il/~joel<http://www.weizmann.ac.il/~joel>
Dept. of Structural Biology   tel: +972  (8) 934 6309  
proteopedia.org<http://www.weizmann.ac.il/~joel>
Weizmann Institute of Science fax: +972  (8) 934 6312
Rehovot 76100 ISRAEL  mob: +972 (50) 510 9600
-

On 17Jul, 2019, at 13:00, Susan Lea 
mailto:susan@path.ox.ac.uk>> wrote:

I'll shut up soon

Other than when asked to review, I consider it best to concern myself most with 
how I use the share of the limited resources I have access to and refrain from 
commenting on work by others in fields I have sufficiently little knowledge of 
that my estimate of worth is likely to be flawed.

I certainly do not agree that a structure determined by EM is a priori more 
biologically true than one determined by crystallography - as always the only 
question is exactly what is the structure of, and how has the sample had to be 
compromised to determine it.

If you feel you can prove that this is a flawed statement across the whole of 
biology - publish an article and we can shut the synchrotrons.

Yours - from a mixed-method structural biologist ;-)

Susan

Prof. Susan M. Lea,  FMedSci  tel: +44 1865 275181
--
Director of the Central Oxford Structural Microscopy and Imaging Centre & 
Professor of Microbiology
Sir William Dunn School of Pathology, Oxford OX1 3RE Professorial Fellow @ 
WadhamCollege


From: r...@mrc-lmb.cam.ac.uk<mailto:r...@mrc-lmb.cam.ac.uk> 
mailto:r...@mrc-lmb.cam.ac.uk>>
Sent: 17 July 2019 10:21:42
To: Susan Lea
Cc: ccp4bb@jiscmail.ac.uk<mailto:ccp4bb@jiscmail.ac.uk>
Subject: Re: [ccp4bb] challenges in structural biology

Hi Susan,

We are not naive if we care about using the limited resources of this planet
responsibly. This has nothing to do with whoever's favourite method. I have
nothing against crystallography, it is a beautiful art and has been a success
historically. I have solved plenty of crystal structures myself and will
probably have to keep doing it for a little while. But it is naive to ignore
that the time to move on has arrived, and that we have to use resources to
develop better technologies which address the real biological questions
instead of keeping dinosaurs on life support.

How many of the structures solved on synchrotrons worldwide and of the
zillions in the PDB are of any use or biological relevance (original
question)? There is an enormous amount of waste, including the nasty chemicals
use to grow crystals and to phase pointless structures, let's be honest.

Best wishes,

Radu



I think we are naive if we care about the method used to obtain the structure
- what matters is getting at the structure.  What is great is that the variety
of ways we can do this has increased meaning more samples become tractable for
high resolution structure determination. I don’t see the point of ridiculous
my method is better than your method arguments - for some samples all methods
are equivalent, for some there is only one method that will yield answers - we
just need to train students and develop methods that allow the broadest
access. Everything else is bias-driven posturing. Let’s just solve some
structures and learn something about biology.


Susan

Sent from my iPhone

On 17 Jul 2019, at 08:43, r...@mrc-lmb.cam.ac.uk<mailto:r...@mrc-lmb.cam.ac.uk> 
mailto:r...@mrc-lmb.cam.ac.uk>>
wrote:

Hi Both,

I am not questioning the PDB stats, the issue was whether (crystal)
structures
are sufficiently relevant to address biologic

Re: [ccp4bb] challenges in structural biology

[Loes Kroon-Batenburg]

Dear James,

It would seem to me that an important issue is also: do get all 
information out of our diffraction data? By integrating the Bragg peaks 
we usually neglect the diffuse scattering that could potentially contain 
additional (dynamic) structural information. This can be cloudy diffuse 
scattering hidden in the background but also diffuse streaks that 
contain information on packing disorder and reveals intrinsic 
interactions in the crystal.


Loes Kroon-Batenburg

On 07/15/19 21:44, Holton, James M wrote:

Hello folks,

I have the distinct honor of chairing the next Gordon Research
Conference on Diffraction Methods in Structural Biology (July 26-31
2020).  This meeting will focus on the biggest challenges currently
faced by structural biologists, and I mean actual real-world
challenges.  As much as possible, these challenges will take the form of
friendly competitions with defined parameters, data, a scoring system,
and "winners", to be established along with other unpublished results
only at the meeting, as is tradition at GRCs.

But what are the principle challenges in biological structure
determination today?  I of course have my own ideas, but I feel like I'm
forgetting something.  Obvious choices are:
1) getting crystals to diffract better
2) building models into low-resolution maps (after failing at #1)
3) telling if a ligand is really there or not
4) the phase problem (dealing with weak signal, twinning and
pseudotranslation)
5) what does "resolution" really mean?
6) why are macromolecular R factors so much higher than small-molecule ones?
7) what is the best way to process serial crystallography data?
8) how should one deal with non-isomorphism in multi-crystal methods?
9) what is the "structure" of something that won't sit still?

What am I missing?  Is industry facing different problems than
academics?  Are there specific challenges facing electron-based
techniques?  If so, could the combined strength of all the world's
methods developers solve them?  I'm interested in hearing the voice of
this community.  On or off-list is fine.

-James Holton
MAD Scientist




To unsubscribe from the CCP4BB list, click the following link:
https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1



--

__

Dr. Loes Kroon-Batenburg
Dept. of Crystal and Structural Chemistry
Bijvoet Center for Biomolecular Research
Utrecht University
Padualaan 8, 3584 CH Utrecht
The Netherlands

E-mail : l.m.j.kroon-batenb...@uu.nl
phone  : +31-30-2532865
fax: +31-30-2533940
__



To unsubscribe from the CCP4BB list, click the following link:
https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1

Re: [ccp4bb] challenges in structural biology

[graeme.win...@diamond.ac.uk]

mb.cam.ac.uk> 
mailto:r...@mrc-lmb.cam.ac.uk>>
wrote:

Hi Both,

I am not questioning the PDB stats, the issue was whether (crystal)
structures
are sufficiently relevant to address biological questions and justify the
resources. Fragment screening is one example where investment in protein
crystallography can still be justified (for now). But it doesn't really
ask
or
answer biological questions... for these, whether we like it or not,
macromolecular crystallography (or NMR, even in cell) cannot be the
future.
In
my opinion :-)

Best wishes,

Radu


Stating the crystallography is dead might be a bit premature, it is
still
king
for depositions.



In 2017 we had a large number of fragment screening experiments
deposited.







From: CCP4 bulletin board mailto:CCP4BB@JISCMAIL.AC.UK>> 
On Behalf Of Nukri
Sanishvili
Sent: 15 July 2019 23:09
To: CCP4BB@JISCMAIL.AC.UK<mailto:CCP4BB@JISCMAIL.AC.UK>
Subject: Re: [ccp4bb] challenges in structural biology



I know it is going to hijack the original topic but I could not help...



╲The reports of death of (macromolecular) crystallography are greatly
exaggerated.

If we believed the prognosticators, it has been dead since the 80s when
some
folks made the claim that the only relevant structures were those solved
by
NMR.

I think we've done quite well since then...

Best,

Nukri



On Mon, Jul 15, 2019 at 3:45 PM 
mailto:r...@mrc-lmb.cam.ac.uk>
<mailto:r...@mrc-lmb.cam.ac.uk> > wrote:

Hi Tassos, Tim,

I wonder why would you or anyone on this list worry whether biological
questions that can be asked and answered with structures are relevant to
justify the resources? I think there is abundant evidence that this is
the
case. Unless your point is that crystallography is now dead for all
practical
purposes... then yes, I fully agree :-) It would however be wrong to
erase
its
historical contribution to understanding biology.

Best wishes,

Radu


I would wonder more if the biological questions you can *ask* with a
(crystal)
structure are sufficiently relevant to justify the resources.

Sent from my iPhone

On 15 Jul 2019, at 22:08, Tim GrÃπne 
mailto:tim.gru...@univie.ac.at>
<mailto:tim.gru...@univie.ac.at> > wrote:

Dear James,

10) are the biological questions that you can answer with a (crystal)
structure sufficiently relevant to justify the resources?

Best,
Tim



Am 15.07.2019 21:44, schrieb Holton, James M:
Hello folks,
I have the distinct honor of chairing the next Gordon Research
Conference on Diffraction Methods in Structural Biology (July 26-31
2020).  This meeting will focus on the biggest challenges currently
faced by structural biologists, and I mean actual real-world
challenges.  As much as possible, these challenges will take the form
of
friendly competitions with defined parameters, data, a scoring
system,
and "winners", to be established along with other unpublished results
only at the meeting, as is tradition at GRCs.
But what are the principle challenges in biological structure
determination today?  I of course have my own ideas, but I feel like
I'm
forgetting something.  Obvious choices are:
1) getting crystals to diffract better
2) building models into low-resolution maps (after failing at #1)
3) telling if a ligand is really there or not
4) the phase problem (dealing with weak signal, twinning and
pseudotranslation)
5) what does "resolution" really mean?
6) why are macromolecular R factors so much higher than
small-molecule
ones?
7) what is the best way to process serial crystallography data?
8) how should one deal with non-isomorphism in multi-crystal methods?
9) what is the "structure" of something that won't sit still?
What am I missing?  Is industry facing different problems than
academics?  Are there specific challenges facing electron-based
techniques?  If so, could the combined strength of all the world's
methods developers solve them?  I'm interested in hearing the voice
of
this community.  On or off-list is fine.
-James Holton
MAD Scientist

To unsubscribe from the CCP4BB list, click the following link:
https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB
<https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1> =1

--
--
Tim Gruene
Head of the Centre for X-ray Structure Analysis
Faculty of Chemistry
University of Vienna

Phone: +43-1-4277-70202

GPG Key ID = A46BEE1A



To unsubscribe from the CCP4BB list, click the following link:
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<https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1> =1



To unsubscribe from the CCP4BB list, click the following link:
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<https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1> =1

Re: [ccp4bb] challenges in structural biology

[Joel Sussman]

Dear James
Another key point, which is directly related to the discussion of 'why' one 
does a particular structural study, is:
how one explains the results to others, including even to 'non structural 
biologists’.
This is important and INDEPENDENT of the particular experimental procedure. 
Some examples of possible ways to this can be seen in Proteopedia,
e.g.
* Insulin  - http://proteopedia.org/w/Insulin
* Tutorial:How do we get the oxygen we breathe - 
http://proteopedia.org/w/Tutorial:How_do_we_get_the_oxygen_we_breathe
* Immunodeficiency virus protease - 
http://proteopedia.org/w/Immunodeficiency_virus_protease
* An Interactive 3D Complement to a 'Molecular Cell' paper - 
http://proteopedia.org/w/Journal:Molecular_Cell:1

Joel


Prof. Joel L. Sussman  
joel.suss...@weizmann.ac.il<mailto:joel.suss...@weizmann.ac.il>   
www.weizmann.ac.il/~joel<http://www.weizmann.ac.il/~joel>
Dept. of Structural Biology   tel: +972  (8) 934 6309  
proteopedia.org<http://www.weizmann.ac.il/~joel>
Weizmann Institute of Science fax: +972  (8) 934 6312
Rehovot 76100 ISRAEL  mob: +972 (50) 510 9600
-

On 17Jul, 2019, at 13:00, Susan Lea 
mailto:susan@path.ox.ac.uk>> wrote:

I'll shut up soon

Other than when asked to review, I consider it best to concern myself most with 
how I use the share of the limited resources I have access to and refrain from 
commenting on work by others in fields I have sufficiently little knowledge of 
that my estimate of worth is likely to be flawed.

I certainly do not agree that a structure determined by EM is a priori more 
biologically true than one determined by crystallography - as always the only 
question is exactly what is the structure of, and how has the sample had to be 
compromised to determine it.

If you feel you can prove that this is a flawed statement across the whole of 
biology - publish an article and we can shut the synchrotrons.

Yours - from a mixed-method structural biologist ;-)

Susan

Prof. Susan M. Lea,  FMedSci  tel: +44 1865 275181
--
Director of the Central Oxford Structural Microscopy and Imaging Centre & 
Professor of Microbiology
Sir William Dunn School of Pathology, Oxford OX1 3RE Professorial Fellow @ 
WadhamCollege


From: r...@mrc-lmb.cam.ac.uk<mailto:r...@mrc-lmb.cam.ac.uk> 
mailto:r...@mrc-lmb.cam.ac.uk>>
Sent: 17 July 2019 10:21:42
To: Susan Lea
Cc: ccp4bb@jiscmail.ac.uk<mailto:ccp4bb@jiscmail.ac.uk>
Subject: Re: [ccp4bb] challenges in structural biology

Hi Susan,

We are not naive if we care about using the limited resources of this planet
responsibly. This has nothing to do with whoever's favourite method. I have
nothing against crystallography, it is a beautiful art and has been a success
historically. I have solved plenty of crystal structures myself and will
probably have to keep doing it for a little while. But it is naive to ignore
that the time to move on has arrived, and that we have to use resources to
develop better technologies which address the real biological questions
instead of keeping dinosaurs on life support.

How many of the structures solved on synchrotrons worldwide and of the
zillions in the PDB are of any use or biological relevance (original
question)? There is an enormous amount of waste, including the nasty chemicals
use to grow crystals and to phase pointless structures, let's be honest.

Best wishes,

Radu



I think we are naive if we care about the method used to obtain the structure
- what matters is getting at the structure.  What is great is that the variety
of ways we can do this has increased meaning more samples become tractable for
high resolution structure determination. I don’t see the point of ridiculous
my method is better than your method arguments - for some samples all methods
are equivalent, for some there is only one method that will yield answers - we
just need to train students and develop methods that allow the broadest
access. Everything else is bias-driven posturing. Let’s just solve some
structures and learn something about biology.


Susan

Sent from my iPhone

On 17 Jul 2019, at 08:43, r...@mrc-lmb.cam.ac.uk<mailto:r...@mrc-lmb.cam.ac.uk> 
mailto:r...@mrc-lmb.cam.ac.uk>>
wrote:

Hi Both,

I am not questioning the PDB stats, the issue was whether (crystal)
structures
are sufficiently relevant to address biological questions and justify the
resources. Fragment screening is one example where investment in protein
crystallography can still be justified (for now). But it doesn't really ask
or
answer biological questions... for these, whether we like it or not,
macromolecular crystallography (or NMR, e

Re: [ccp4bb] challenges in structural biology

[Bärbel Blaum]

ng the PDB stats, the issue was whether (crystal)
>>>> structures
>>>> are sufficiently relevant to address biological questions and justify 
the
>>>> resources. Fragment screening is one example where investment in 
protein
>>>> crystallography can still be justified (for now). But it doesn't really
>>>> ask
>>>> or
>>>> answer biological questions... for these, whether we like it or not,
>>>> macromolecular crystallography (or NMR, even in cell) cannot be the
>>>> future.
>>>> In
>>>> my opinion :-)
>>>>
>>>> Best wishes,
>>>>
>>>> Radu
>>>>
>>>>
>>>>> Stating the crystallography is dead might be a bit premature, it is
>>>>> still
>>>>> king
>>>>> for depositions.
>>>>>
>>>>>
>>>>>
>>>>> In 2017 we had a large number of fragment screening experiments
>>>>> deposited.
>>>>>
>>>>>
>>>>>
>>>>>
>>>>>
>>>>>
>>>>>
>>>>> From: CCP4 bulletin board  On Behalf Of Nukri
>>>>> Sanishvili
>>>>> Sent: 15 July 2019 23:09
>>>>> To: CCP4BB@JISCMAIL.AC.UK
>>>>> Subject: Re: [ccp4bb] challenges in structural biology
>>>>>
>>>>>
>>>>>
>>>>> I know it is going to hijack the original topic but I could not 
help...
>>>>>
>>>>>
>>>>>
>>>>> ╲The reports of death of (macromolecular) crystallography are 
greatly
>>>>> exaggerated.
>>>>>
>>>>> If we believed the prognosticators, it has been dead since the 80s 
when
>>>>> some
>>>>> folks made the claim that the only relevant structures were those 
solved
>>>>> by
>>>>> NMR.
>>>>>
>>>>> I think we've done quite well since then...
>>>>>
>>>>> Best,
>>>>>
>>>>> Nukri
>>>>>
>>>>>
>>>>>
>>>>> On Mon, Jul 15, 2019 at 3:45 PM >>>> <mailto:r...@mrc-lmb.cam.ac.uk> > wrote:
>>>>>
>>>>> Hi Tassos, Tim,
>>>>>
>>>>> I wonder why would you or anyone on this list worry whether biological
>>>>> questions that can be asked and answered with structures are relevant 
to
>>>>> justify the resources? I think there is abundant evidence that this is
>>>>> the
>>>>> case. Unless your point is that crystallography is now dead for all
>>>>> practical
>>>>> purposes... then yes, I fully agree :-) It would however be wrong to
>>>>> erase
>>>>> its
>>>>> historical contribution to understanding biology.
>>>>>
>>>>> Best wishes,
>>>>>
>>>>> Radu
>>>>>
>>>>>
>>>>>> I would wonder more if the biological questions you can *ask* with a
>>>>>> (crystal)
>>>>>> structure are sufficiently relevant to justify the resources.
>>>>>>
>>>>>> Sent from my iPhone
>>>>>>
>>>>>>> On 15 Jul 2019, at 22:08, Tim GrÃπne >>>>>> <mailto:tim.gru...@univie.ac.at> > wrote:
>>>>>>>
>>>>>>> Dear James,
>>>>>>>
>>>>>>> 10) are the biological questions that you can answer with a 
(crystal)
>>>>>>> structure sufficiently relevant to justify the resources?
>>>>>>>
>>>>>>> Best,
>>>>>>> Tim
>>>>>>>
>>>>>>>
>>>>>>>
>>>>>>> Am 15.07.2019 21:44, schrieb Holton, James M:
>>>>>>>> Hello folks,
>>>>>>>> I have the distinct honor of chairing the next Gordon Research
>>>>>>>> Conference on Diffract

Re: [ccp4bb] challenges in structural biology

[Scapin, Giovanna]

Couldn’t agree more.  And I think more discussion on integrating all the 
different methods (including bioSAXS and HDX) would be a good topic

Giovanna 

> On Jul 17, 2019, at 4:18 AM, Tristan Croll  wrote:
> 
> EXTERNAL EMAIL – Use caution with any links or file attachments.
> 
> Hi Radu,
> 
> Barring some truly spectacular advances, I think that crystallography is 
> going to have a major role to play for a long time yet. Looking at 
> single-particle cryoEM, for almost every target apart from the few 
> ultra-rigid "rocks" the reconstruction will have a wide range of resolutions 
> from (near)atomic in the rigid core to fuzzy blobs out on the floppy 
> exterior. Yes, modern focused reconstruction techniques are improving upon 
> this all the time, but there will be limits - and the problem is much more 
> serious when it comes to electron cryo-tomography methods where you can't 
> simply collect more particles! I think there's some lovely potential 
> complementarity between cryo-EM and crystallography here: almost by 
> definition, these peripheral mobile domains tend to be things that fold 
> independently of the main body of the complex - so why not express them 
> independently and see if they crystallise? That way you get the best of both 
> worlds: the initial cryo-EM reconstruction allows some informed decision 
> making on what construct(s) is/are likely to reliably crystallise, 
> crystallisation of those domains gives you the atomic-resolution description 
> you need, and modelling these back into the cryo-EM map allows you to study 
> them in a more natural context.
> 
> To bring things back to the original topic, I guess that's what I'd like to 
> see more of: rather than seeing the methods as in fundamental competition, 
> where are the *complementarities* between crystallography and newer 
> techniques?
> 
> Best regards,
> 
> Tristan
> 
>> On 2019-07-17 08:43, r...@mrc-lmb.cam.ac.uk wrote:
>> Hi Both,
>> I am not questioning the PDB stats, the issue was whether (crystal) 
>> structures
>> are sufficiently relevant to address biological questions and justify the
>> resources. Fragment screening is one example where investment in protein
>> crystallography can still be justified (for now). But it doesn't really ask 
>> or
>> answer biological questions... for these, whether we like it or not,
>> macromolecular crystallography (or NMR, even in cell) cannot be the future. 
>> In
>> my opinion :-)
>> Best wishes,
>> Radu
>>> Stating the crystallography is dead might be a bit premature, it is still 
>>> king
>>> for depositions.
>>> In 2017 we had a large number of fragment screening experiments deposited.
>>> From: CCP4 bulletin board  On Behalf Of Nukri
>>> Sanishvili
>>> Sent: 15 July 2019 23:09
>>> To: CCP4BB@JISCMAIL.AC.UK
>>> Subject: Re: [ccp4bb] challenges in structural biology
>>> I know it is going to hijack the original topic but I could not help...
>>> “The reports of death of (macromolecular) crystallography are greatly
>>> exaggerated.
>>> If we believed the prognosticators, it has been dead since the 80s when some
>>> folks made the claim that the only relevant structures were those solved by
>>> NMR.
>>> I think we've done quite well since then...
>>> Best,
>>> Nukri
>>> On Mon, Jul 15, 2019 at 3:45 PM >> <mailto:r...@mrc-lmb.cam.ac.uk> > wrote:
>>> Hi Tassos, Tim,
>>> I wonder why would you or anyone on this list worry whether biological
>>> questions that can be asked and answered with structures are relevant to
>>> justify the resources? I think there is abundant evidence that this is the
>>> case. Unless your point is that crystallography is now dead for all 
>>> practical
>>> purposes... then yes, I fully agree :-) It would however be wrong to erase 
>>> its
>>> historical contribution to understanding biology.
>>> Best wishes,
>>> Radu
>>>> I would wonder more if the biological questions you can *ask* with a
>>>> (crystal)
>>>> structure are sufficiently relevant to justify the resources.
>>>> Sent from my iPhone
>>>>> On 15 Jul 2019, at 22:08, Tim Grüne >>>> <mailto:tim.gru...@univie.ac.at> > wrote:
>>>>> Dear James,
>>>>> 10) are the biological questions that you can answer with a (crystal)
>>>>> structure sufficiently relevant to justify the resources?
>>>>> Best,
>>>>> Tim
>>>>> Am 15.07.2019 21:44, schrieb Ho

Re: [ccp4bb] challenges in structural biology

[Susan Lea]

I'll shut up soon

Other than when asked to review, I consider it best to concern myself most with 
how I use the share of the limited resources I have access to and refrain from 
commenting on work by others in fields I have sufficiently little knowledge of 
that my estimate of worth is likely to be flawed.

I certainly do not agree that a structure determined by EM is a priori more 
biologically true than one determined by crystallography - as always the only 
question is exactly what is the structure of, and how has the sample had to be 
compromised to determine it.

If you feel you can prove that this is a flawed statement across the whole of 
biology - publish an article and we can shut the synchrotrons.

Yours - from a mixed-method structural biologist ;-)

Susan

Prof. Susan M. Lea,  FMedSci  tel: +44 1865 275181
--
Director of the Central Oxford Structural Microscopy and Imaging Centre & 
Professor of Microbiology
Sir William Dunn School of Pathology, Oxford OX1 3RE Professorial Fellow @ 
WadhamCollege


From: r...@mrc-lmb.cam.ac.uk 
Sent: 17 July 2019 10:21:42
To: Susan Lea
Cc: ccp4bb@jiscmail.ac.uk
Subject: Re: [ccp4bb] challenges in structural biology

Hi Susan,

We are not naive if we care about using the limited resources of this planet
responsibly. This has nothing to do with whoever's favourite method. I have
nothing against crystallography, it is a beautiful art and has been a success
historically. I have solved plenty of crystal structures myself and will
probably have to keep doing it for a little while. But it is naive to ignore
that the time to move on has arrived, and that we have to use resources to
develop better technologies which address the real biological questions
instead of keeping dinosaurs on life support.

How many of the structures solved on synchrotrons worldwide and of the
zillions in the PDB are of any use or biological relevance (original
question)? There is an enormous amount of waste, including the nasty chemicals
use to grow crystals and to phase pointless structures, let's be honest.

Best wishes,

Radu



> I think we are naive if we care about the method used to obtain the structure
> - what matters is getting at the structure.  What is great is that the variety
> of ways we can do this has increased meaning more samples become tractable for
> high resolution structure determination. I don’t see the point of ridiculous
> my method is better than your method arguments - for some samples all methods
> are equivalent, for some there is only one method that will yield answers - we
> just need to train students and develop methods that allow the broadest
> access. Everything else is bias-driven posturing. Let’s just solve some
> structures and learn something about biology.
>
>
> Susan
>
> Sent from my iPhone
>
>> On 17 Jul 2019, at 08:43, r...@mrc-lmb.cam.ac.uk 
>> wrote:
>>
>> Hi Both,
>>
>> I am not questioning the PDB stats, the issue was whether (crystal)
>> structures
>> are sufficiently relevant to address biological questions and justify the
>> resources. Fragment screening is one example where investment in protein
>> crystallography can still be justified (for now). But it doesn't really ask
>> or
>> answer biological questions... for these, whether we like it or not,
>> macromolecular crystallography (or NMR, even in cell) cannot be the future.
>> In
>> my opinion :-)
>>
>> Best wishes,
>>
>> Radu
>>
>>
>>> Stating the crystallography is dead might be a bit premature, it is still
>>> king
>>> for depositions.
>>>
>>>
>>>
>>> In 2017 we had a large number of fragment screening experiments deposited.
>>>
>>>
>>>
>>>
>>>
>>>
>>>
>>> From: CCP4 bulletin board  On Behalf Of Nukri
>>> Sanishvili
>>> Sent: 15 July 2019 23:09
>>> To: CCP4BB@JISCMAIL.AC.UK
>>> Subject: Re: [ccp4bb] challenges in structural biology
>>>
>>>
>>>
>>> I know it is going to hijack the original topic but I could not help...
>>>
>>>
>>>
>>> “The reports of death of (macromolecular) crystallography are greatly
>>> exaggerated.
>>>
>>> If we believed the prognosticators, it has been dead since the 80s when
>>> some
>>> folks made the claim that the only relevant structures were those solved
>>> by
>>> NMR.
>>>
>>> I think we've done quite well since then...
>>>
>>> Best,
>>>
>>> Nukri
>>>
>>>
>>

Re: [ccp4bb] challenges in structural biology

[radu]

Hi Paul,

Fair point, apologies if anyone was offended by my comments! I simply thought
that such matters are meaningful for this forum. I am just as guilty as
everyone, and it is important to put our work into the broader perspective
from time to time.

Best wishes,

Radu


> Hi Radu and all
>
> Could i humbly suggest some careful reflection before this ends up polarising
> the amazing structural biology community. Since the year dot everyone has been
> contributing to integrated approaches and I fear that the tone of this debate
> will create much negativity around the community which seems pointless at
> least to me..
>
> Maybe a commentary published somewhere would be a better way to debate what
> are important issues and not through the  CCP4 forum?
>
> best wishes
>
> Paul
>
>
>
>
>> On 17 Jul 2019, at 10:21, r...@mrc-lmb.cam.ac.uk wrote:
>>
>> Hi Susan,
>>
>> We are not naive if we care about using the limited resources of this
>> planet
>> responsibly. This has nothing to do with whoever's favourite method. I have
>> nothing against crystallography, it is a beautiful art and has been a
>> success
>> historically. I have solved plenty of crystal structures myself and will
>> probably have to keep doing it for a little while. But it is naive to
>> ignore
>> that the time to move on has arrived, and that we have to use resources to
>> develop better technologies which address the real biological questions
>> instead of keeping dinosaurs on life support.
>>
>> How many of the structures solved on synchrotrons worldwide and of the
>> zillions in the PDB are of any use or biological relevance (original
>> question)? There is an enormous amount of waste, including the nasty
>> chemicals
>> use to grow crystals and to phase pointless structures, let's be honest.
>>
>> Best wishes,
>>
>> Radu
>>
>>
>>
>>> I think we are naive if we care about the method used to obtain the
>>> structure
>>> - what matters is getting at the structure.  What is great is that the
>>> variety
>>> of ways we can do this has increased meaning more samples become tractable
>>> for
>>> high resolution structure determination. I don’t see the point of
>>> ridiculous
>>> my method is better than your method arguments - for some samples all
>>> methods
>>> are equivalent, for some there is only one method that will yield answers -
>>> we
>>> just need to train students and develop methods that allow the broadest
>>> access. Everything else is bias-driven posturing. Let’s just solve some
>>> structures and learn something about biology.
>>>
>>>
>>> Susan
>>>
>>> Sent from my iPhone
>>>
>>>> On 17 Jul 2019, at 08:43, r...@mrc-lmb.cam.ac.uk 
>>>> wrote:
>>>>
>>>> Hi Both,
>>>>
>>>> I am not questioning the PDB stats, the issue was whether (crystal)
>>>> structures
>>>> are sufficiently relevant to address biological questions and justify the
>>>> resources. Fragment screening is one example where investment in protein
>>>> crystallography can still be justified (for now). But it doesn't really
>>>> ask
>>>> or
>>>> answer biological questions... for these, whether we like it or not,
>>>> macromolecular crystallography (or NMR, even in cell) cannot be the
>>>> future.
>>>> In
>>>> my opinion :-)
>>>>
>>>> Best wishes,
>>>>
>>>> Radu
>>>>
>>>>
>>>>> Stating the crystallography is dead might be a bit premature, it is
>>>>> still
>>>>> king
>>>>> for depositions.
>>>>>
>>>>>
>>>>>
>>>>> In 2017 we had a large number of fragment screening experiments
>>>>> deposited.
>>>>>
>>>>>
>>>>>
>>>>>
>>>>>
>>>>>
>>>>>
>>>>> From: CCP4 bulletin board  On Behalf Of Nukri
>>>>> Sanishvili
>>>>> Sent: 15 July 2019 23:09
>>>>> To: CCP4BB@JISCMAIL.AC.UK
>>>>> Subject: Re: [ccp4bb] challenges in structural biology
>>>>>
>>>>>
>>>>>
>>>>> I know it is going to hijack the original topic but I could not help...
>>>>>
>>>>>
>>>>>
>>>>> “The reports of deat

Re: [ccp4bb] challenges in structural biology

[Freemont, Paul S]

Hi Radu and all

Could i humbly suggest some careful reflection before this ends up polarising 
the amazing structural biology community. Since the year dot everyone has been 
contributing to integrated approaches and I fear that the tone of this debate 
will create much negativity around the community which seems pointless at least 
to me..

Maybe a commentary published somewhere would be a better way to debate what are 
important issues and not through the  CCP4 forum?

best wishes

Paul




> On 17 Jul 2019, at 10:21, r...@mrc-lmb.cam.ac.uk wrote:
> 
> Hi Susan,
> 
> We are not naive if we care about using the limited resources of this planet
> responsibly. This has nothing to do with whoever's favourite method. I have
> nothing against crystallography, it is a beautiful art and has been a success
> historically. I have solved plenty of crystal structures myself and will
> probably have to keep doing it for a little while. But it is naive to ignore
> that the time to move on has arrived, and that we have to use resources to
> develop better technologies which address the real biological questions
> instead of keeping dinosaurs on life support.
> 
> How many of the structures solved on synchrotrons worldwide and of the
> zillions in the PDB are of any use or biological relevance (original
> question)? There is an enormous amount of waste, including the nasty chemicals
> use to grow crystals and to phase pointless structures, let's be honest.
> 
> Best wishes,
> 
> Radu
> 
> 
> 
>> I think we are naive if we care about the method used to obtain the structure
>> - what matters is getting at the structure.  What is great is that the 
>> variety
>> of ways we can do this has increased meaning more samples become tractable 
>> for
>> high resolution structure determination. I don’t see the point of ridiculous
>> my method is better than your method arguments - for some samples all methods
>> are equivalent, for some there is only one method that will yield answers - 
>> we
>> just need to train students and develop methods that allow the broadest
>> access. Everything else is bias-driven posturing. Let’s just solve some
>> structures and learn something about biology.
>> 
>> 
>> Susan
>> 
>> Sent from my iPhone
>> 
>>> On 17 Jul 2019, at 08:43, r...@mrc-lmb.cam.ac.uk 
>>> wrote:
>>> 
>>> Hi Both,
>>> 
>>> I am not questioning the PDB stats, the issue was whether (crystal)
>>> structures
>>> are sufficiently relevant to address biological questions and justify the
>>> resources. Fragment screening is one example where investment in protein
>>> crystallography can still be justified (for now). But it doesn't really ask
>>> or
>>> answer biological questions... for these, whether we like it or not,
>>> macromolecular crystallography (or NMR, even in cell) cannot be the future.
>>> In
>>> my opinion :-)
>>> 
>>> Best wishes,
>>> 
>>> Radu
>>> 
>>> 
>>>> Stating the crystallography is dead might be a bit premature, it is still
>>>> king
>>>> for depositions.
>>>> 
>>>> 
>>>> 
>>>> In 2017 we had a large number of fragment screening experiments deposited.
>>>> 
>>>> 
>>>> 
>>>> 
>>>> 
>>>> 
>>>> 
>>>> From: CCP4 bulletin board  On Behalf Of Nukri
>>>> Sanishvili
>>>> Sent: 15 July 2019 23:09
>>>> To: CCP4BB@JISCMAIL.AC.UK
>>>> Subject: Re: [ccp4bb] challenges in structural biology
>>>> 
>>>> 
>>>> 
>>>> I know it is going to hijack the original topic but I could not help...
>>>> 
>>>> 
>>>> 
>>>> “The reports of death of (macromolecular) crystallography are greatly
>>>> exaggerated.
>>>> 
>>>> If we believed the prognosticators, it has been dead since the 80s when
>>>> some
>>>> folks made the claim that the only relevant structures were those solved
>>>> by
>>>> NMR.
>>>> 
>>>> I think we've done quite well since then...
>>>> 
>>>> Best,
>>>> 
>>>> Nukri
>>>> 
>>>> 
>>>> 
>>>> On Mon, Jul 15, 2019 at 3:45 PM >>> <mailto:r...@mrc-lmb.cam.ac.uk> > wrote:
>>>> 
>>>> Hi Tassos, Tim,
>>>> 
>>>> I wonder why would you or anyone on this list wo

Re: [ccp4bb] challenges in structural biology

[radu]

Hi Susan,

We are not naive if we care about using the limited resources of this planet
responsibly. This has nothing to do with whoever's favourite method. I have
nothing against crystallography, it is a beautiful art and has been a success
historically. I have solved plenty of crystal structures myself and will
probably have to keep doing it for a little while. But it is naive to ignore
that the time to move on has arrived, and that we have to use resources to
develop better technologies which address the real biological questions
instead of keeping dinosaurs on life support.

How many of the structures solved on synchrotrons worldwide and of the
zillions in the PDB are of any use or biological relevance (original
question)? There is an enormous amount of waste, including the nasty chemicals
use to grow crystals and to phase pointless structures, let's be honest.

Best wishes,

Radu



> I think we are naive if we care about the method used to obtain the structure
> - what matters is getting at the structure.  What is great is that the variety
> of ways we can do this has increased meaning more samples become tractable for
> high resolution structure determination. I don’t see the point of ridiculous
> my method is better than your method arguments - for some samples all methods
> are equivalent, for some there is only one method that will yield answers - we
> just need to train students and develop methods that allow the broadest
> access. Everything else is bias-driven posturing. Let’s just solve some
> structures and learn something about biology.
>
>
> Susan
>
> Sent from my iPhone
>
>> On 17 Jul 2019, at 08:43, r...@mrc-lmb.cam.ac.uk 
>> wrote:
>>
>> Hi Both,
>>
>> I am not questioning the PDB stats, the issue was whether (crystal)
>> structures
>> are sufficiently relevant to address biological questions and justify the
>> resources. Fragment screening is one example where investment in protein
>> crystallography can still be justified (for now). But it doesn't really ask
>> or
>> answer biological questions... for these, whether we like it or not,
>> macromolecular crystallography (or NMR, even in cell) cannot be the future.
>> In
>> my opinion :-)
>>
>> Best wishes,
>>
>> Radu
>>
>>
>>> Stating the crystallography is dead might be a bit premature, it is still
>>> king
>>> for depositions.
>>>
>>>
>>>
>>> In 2017 we had a large number of fragment screening experiments deposited.
>>>
>>>
>>>
>>>
>>>
>>>
>>>
>>> From: CCP4 bulletin board  On Behalf Of Nukri
>>> Sanishvili
>>> Sent: 15 July 2019 23:09
>>> To: CCP4BB@JISCMAIL.AC.UK
>>> Subject: Re: [ccp4bb] challenges in structural biology
>>>
>>>
>>>
>>> I know it is going to hijack the original topic but I could not help...
>>>
>>>
>>>
>>> “The reports of death of (macromolecular) crystallography are greatly
>>> exaggerated.
>>>
>>> If we believed the prognosticators, it has been dead since the 80s when
>>> some
>>> folks made the claim that the only relevant structures were those solved
>>> by
>>> NMR.
>>>
>>> I think we've done quite well since then...
>>>
>>> Best,
>>>
>>> Nukri
>>>
>>>
>>>
>>> On Mon, Jul 15, 2019 at 3:45 PM >> <mailto:r...@mrc-lmb.cam.ac.uk> > wrote:
>>>
>>> Hi Tassos, Tim,
>>>
>>> I wonder why would you or anyone on this list worry whether biological
>>> questions that can be asked and answered with structures are relevant to
>>> justify the resources? I think there is abundant evidence that this is the
>>> case. Unless your point is that crystallography is now dead for all
>>> practical
>>> purposes... then yes, I fully agree :-) It would however be wrong to erase
>>> its
>>> historical contribution to understanding biology.
>>>
>>> Best wishes,
>>>
>>> Radu
>>>
>>>
>>>> I would wonder more if the biological questions you can *ask* with a
>>>> (crystal)
>>>> structure are sufficiently relevant to justify the resources.
>>>>
>>>> Sent from my iPhone
>>>>
>>>>> On 15 Jul 2019, at 22:08, Tim Grüne >>>> <mailto:tim.gru...@univie.ac.at> > wrote:
>>>>>
>>>>> Dear James,
>>>>>
>>>>> 10) are the biological questions that you can answer 

Re: [ccp4bb] challenges in structural biology

[Paula Salgado]

Very well said, Susan! I totally agree and thank you for saying it so clearly 
and eloquently!


Best wishes

Paula


===

Dr Paula S. Salgado
Senior Lecturer in Macromolecular Crystallography
Institute for Cell and Molecular Biosciences
Faculty of Medical Sciences
3rd Floor Cookson Building
Newcastle University
Newcastle upon Tyne, NE2 4HH, UK

Tel: +44 (0)191 208 7432
Fax: +44 (0)191 208 7424
Email: paula.salg...@ncl.ac.uk

From: CCP4 bulletin board  on behalf of Susan Lea 

Sent: 17 July 2019 09:43:29
To: CCP4BB@JISCMAIL.AC.UK 
Subject: Re: [ccp4bb] challenges in structural biology

I think we are naive if we care about the method used to obtain the structure - 
what matters is getting at the structure.  What is great is that the variety of 
ways we can do this has increased meaning more samples become tractable for 
high resolution structure determination. I don’t see the point of ridiculous my 
method is better than your method arguments - for some samples all methods are 
equivalent, for some there is only one method that will yield answers - we just 
need to train students and develop methods that allow the broadest access. 
Everything else is bias-driven posturing. Let’s just solve some structures and 
learn something about biology.


Susan

Sent from my iPhone

> On 17 Jul 2019, at 08:43, r...@mrc-lmb.cam.ac.uk  
> wrote:
>
> Hi Both,
>
> I am not questioning the PDB stats, the issue was whether (crystal) structures
> are sufficiently relevant to address biological questions and justify the
> resources. Fragment screening is one example where investment in protein
> crystallography can still be justified (for now). But it doesn't really ask or
> answer biological questions... for these, whether we like it or not,
> macromolecular crystallography (or NMR, even in cell) cannot be the future. In
> my opinion :-)
>
> Best wishes,
>
> Radu
>
>
>> Stating the crystallography is dead might be a bit premature, it is still 
>> king
>> for depositions.
>>
>>
>>
>> In 2017 we had a large number of fragment screening experiments deposited.
>>
>>
>>
>>
>>
>>
>>
>> From: CCP4 bulletin board  On Behalf Of Nukri
>> Sanishvili
>> Sent: 15 July 2019 23:09
>> To: CCP4BB@JISCMAIL.AC.UK
>> Subject: Re: [ccp4bb] challenges in structural biology
>>
>>
>>
>> I know it is going to hijack the original topic but I could not help...
>>
>>
>>
>> “The reports of death of (macromolecular) crystallography are greatly
>> exaggerated.
>>
>> If we believed the prognosticators, it has been dead since the 80s when some
>> folks made the claim that the only relevant structures were those solved by
>> NMR.
>>
>> I think we've done quite well since then...
>>
>> Best,
>>
>> Nukri
>>
>>
>>
>> On Mon, Jul 15, 2019 at 3:45 PM > <mailto:r...@mrc-lmb.cam.ac.uk> > wrote:
>>
>> Hi Tassos, Tim,
>>
>> I wonder why would you or anyone on this list worry whether biological
>> questions that can be asked and answered with structures are relevant to
>> justify the resources? I think there is abundant evidence that this is the
>> case. Unless your point is that crystallography is now dead for all practical
>> purposes... then yes, I fully agree :-) It would however be wrong to erase 
>> its
>> historical contribution to understanding biology.
>>
>> Best wishes,
>>
>> Radu
>>
>>
>>> I would wonder more if the biological questions you can *ask* with a
>>> (crystal)
>>> structure are sufficiently relevant to justify the resources.
>>>
>>> Sent from my iPhone
>>>
>>>> On 15 Jul 2019, at 22:08, Tim Grüne >>> <mailto:tim.gru...@univie.ac.at> > wrote:
>>>>
>>>> Dear James,
>>>>
>>>> 10) are the biological questions that you can answer with a (crystal)
>>>> structure sufficiently relevant to justify the resources?
>>>>
>>>> Best,
>>>> Tim
>>>>
>>>>
>>>>
>>>> Am 15.07.2019 21:44, schrieb Holton, James M:
>>>>> Hello folks,
>>>>> I have the distinct honor of chairing the next Gordon Research
>>>>> Conference on Diffraction Methods in Structural Biology (July 26-31
>>>>> 2020).  This meeting will focus on the biggest challenges currently
>>>>> faced by structural biologists, and I mean actual real-world
>>>>> challenges.  As much as possible, these challenges will take 

Re: [ccp4bb] challenges in structural biology

[Susan Lea]

I think we are naive if we care about the method used to obtain the structure - 
what matters is getting at the structure.  What is great is that the variety of 
ways we can do this has increased meaning more samples become tractable for 
high resolution structure determination. I don’t see the point of ridiculous my 
method is better than your method arguments - for some samples all methods are 
equivalent, for some there is only one method that will yield answers - we just 
need to train students and develop methods that allow the broadest access. 
Everything else is bias-driven posturing. Let’s just solve some structures and 
learn something about biology.


Susan 

Sent from my iPhone

> On 17 Jul 2019, at 08:43, r...@mrc-lmb.cam.ac.uk  
> wrote:
> 
> Hi Both,
> 
> I am not questioning the PDB stats, the issue was whether (crystal) structures
> are sufficiently relevant to address biological questions and justify the
> resources. Fragment screening is one example where investment in protein
> crystallography can still be justified (for now). But it doesn't really ask or
> answer biological questions... for these, whether we like it or not,
> macromolecular crystallography (or NMR, even in cell) cannot be the future. In
> my opinion :-)
> 
> Best wishes,
> 
> Radu
> 
> 
>> Stating the crystallography is dead might be a bit premature, it is still 
>> king
>> for depositions.
>> 
>> 
>> 
>> In 2017 we had a large number of fragment screening experiments deposited.
>> 
>> 
>> 
>> 
>> 
>> 
>> 
>> From: CCP4 bulletin board  On Behalf Of Nukri
>> Sanishvili
>> Sent: 15 July 2019 23:09
>> To: CCP4BB@JISCMAIL.AC.UK
>> Subject: Re: [ccp4bb] challenges in structural biology
>> 
>> 
>> 
>> I know it is going to hijack the original topic but I could not help...
>> 
>> 
>> 
>> “The reports of death of (macromolecular) crystallography are greatly
>> exaggerated.
>> 
>> If we believed the prognosticators, it has been dead since the 80s when some
>> folks made the claim that the only relevant structures were those solved by
>> NMR.
>> 
>> I think we've done quite well since then...
>> 
>> Best,
>> 
>> Nukri
>> 
>> 
>> 
>> On Mon, Jul 15, 2019 at 3:45 PM > <mailto:r...@mrc-lmb.cam.ac.uk> > wrote:
>> 
>> Hi Tassos, Tim,
>> 
>> I wonder why would you or anyone on this list worry whether biological
>> questions that can be asked and answered with structures are relevant to
>> justify the resources? I think there is abundant evidence that this is the
>> case. Unless your point is that crystallography is now dead for all practical
>> purposes... then yes, I fully agree :-) It would however be wrong to erase 
>> its
>> historical contribution to understanding biology.
>> 
>> Best wishes,
>> 
>> Radu
>> 
>> 
>>> I would wonder more if the biological questions you can *ask* with a
>>> (crystal)
>>> structure are sufficiently relevant to justify the resources.
>>> 
>>> Sent from my iPhone
>>> 
>>>> On 15 Jul 2019, at 22:08, Tim Grüne >>> <mailto:tim.gru...@univie.ac.at> > wrote:
>>>> 
>>>> Dear James,
>>>> 
>>>> 10) are the biological questions that you can answer with a (crystal)
>>>> structure sufficiently relevant to justify the resources?
>>>> 
>>>> Best,
>>>> Tim
>>>> 
>>>> 
>>>> 
>>>> Am 15.07.2019 21:44, schrieb Holton, James M:
>>>>> Hello folks,
>>>>> I have the distinct honor of chairing the next Gordon Research
>>>>> Conference on Diffraction Methods in Structural Biology (July 26-31
>>>>> 2020).  This meeting will focus on the biggest challenges currently
>>>>> faced by structural biologists, and I mean actual real-world
>>>>> challenges.  As much as possible, these challenges will take the form of
>>>>> friendly competitions with defined parameters, data, a scoring system,
>>>>> and "winners", to be established along with other unpublished results
>>>>> only at the meeting, as is tradition at GRCs.
>>>>> But what are the principle challenges in biological structure
>>>>> determination today?  I of course have my own ideas, but I feel like I'm
>>>>> forgetting something.  Obvious choices are:
>>>>> 1) getting crystals to diffract better
>>>>> 2) building models int

Re: [ccp4bb] challenges in structural biology

[Tristan Croll]

Hi Radu,

Barring some truly spectacular advances, I think that crystallography is 
going to have a major role to play for a long time yet. Looking at 
single-particle cryoEM, for almost every target apart from the few 
ultra-rigid "rocks" the reconstruction will have a wide range of 
resolutions from (near)atomic in the rigid core to fuzzy blobs out on 
the floppy exterior. Yes, modern focused reconstruction techniques are 
improving upon this all the time, but there will be limits - and the 
problem is much more serious when it comes to electron cryo-tomography 
methods where you can't simply collect more particles! I think there's 
some lovely potential complementarity between cryo-EM and 
crystallography here: almost by definition, these peripheral mobile 
domains tend to be things that fold independently of the main body of 
the complex - so why not express them independently and see if they 
crystallise? That way you get the best of both worlds: the initial 
cryo-EM reconstruction allows some informed decision making on what 
construct(s) is/are likely to reliably crystallise, crystallisation of 
those domains gives you the atomic-resolution description you need, and 
modelling these back into the cryo-EM map allows you to study them in a 
more natural context.


To bring things back to the original topic, I guess that's what I'd like 
to see more of: rather than seeing the methods as in fundamental 
competition, where are the *complementarities* between crystallography 
and newer techniques?


Best regards,

Tristan

On 2019-07-17 08:43, r...@mrc-lmb.cam.ac.uk wrote:

Hi Both,

I am not questioning the PDB stats, the issue was whether (crystal) 
structures
are sufficiently relevant to address biological questions and justify 
the
resources. Fragment screening is one example where investment in 
protein
crystallography can still be justified (for now). But it doesn't really 
ask or

answer biological questions... for these, whether we like it or not,
macromolecular crystallography (or NMR, even in cell) cannot be the 
future. In

my opinion :-)

Best wishes,

Radu


Stating the crystallography is dead might be a bit premature, it is 
still king

for depositions.



In 2017 we had a large number of fragment screening experiments 
deposited.








From: CCP4 bulletin board  On Behalf Of Nukri
Sanishvili
Sent: 15 July 2019 23:09
To: CCP4BB@JISCMAIL.AC.UK
Subject: Re: [ccp4bb] challenges in structural biology



I know it is going to hijack the original topic but I could not 
help...




“The reports of death of (macromolecular) crystallography are 
greatly

exaggerated.

If we believed the prognosticators, it has been dead since the 80s 
when some
folks made the claim that the only relevant structures were those 
solved by

NMR.

I think we've done quite well since then...

Best,

Nukri



On Mon, Jul 15, 2019 at 3:45 PM mailto:r...@mrc-lmb.cam.ac.uk> > wrote:

Hi Tassos, Tim,

I wonder why would you or anyone on this list worry whether biological
questions that can be asked and answered with structures are relevant 
to
justify the resources? I think there is abundant evidence that this is 
the
case. Unless your point is that crystallography is now dead for all 
practical
purposes... then yes, I fully agree :-) It would however be wrong to 
erase its

historical contribution to understanding biology.

Best wishes,

Radu



I would wonder more if the biological questions you can *ask* with a
(crystal)
structure are sufficiently relevant to justify the resources.

Sent from my iPhone


On 15 Jul 2019, at 22:08, Tim Grüne mailto:tim.gru...@univie.ac.at> > wrote:

Dear James,

10) are the biological questions that you can answer with a 
(crystal)

structure sufficiently relevant to justify the resources?

Best,
Tim



Am 15.07.2019 21:44, schrieb Holton, James M:

Hello folks,
I have the distinct honor of chairing the next Gordon Research
Conference on Diffraction Methods in Structural Biology (July 26-31
2020).  This meeting will focus on the biggest challenges currently
faced by structural biologists, and I mean actual real-world
challenges.  As much as possible, these challenges will take the 
form of
friendly competitions with defined parameters, data, a scoring 
system,
and "winners", to be established along with other unpublished 
results

only at the meeting, as is tradition at GRCs.
But what are the principle challenges in biological structure
determination today?  I of course have my own ideas, but I feel 
like I'm

forgetting something.  Obvious choices are:
1) getting crystals to diffract better
2) building models into low-resolution maps (after failing at #1)
3) telling if a ligand is really there or not
4) the phase problem (dealing with weak signal, twinning and
pseudotranslation)
5) what does "resolution" really mean?
6) why are macromolecular R factors so much higher than 
small-molecule

ones?
7) what is the best way to process serial cr

Re: [ccp4bb] challenges in structural biology

[Thomas White]

On Tue, 16 Jul 2019 18:02:20 +
"selina.st...@diamond.ac.uk"  wrote:

> following up on Kay's point, I think it might be worth to discuss
> what we as a community understand by serial crystallography and what
> makes it different from multiple crystal crystallography. I recently
> gave a talk about multiple-crystal and serial crystallography at a
> course and I could not find any textbook definition. Kay's email
> suggests that my understanding differs from his...

I think the usage of the term "serial crystallography" to refer to
cases where you record a small number of rotation exposures from one
crystal isn't very helpful.  I think it's better to reserve "serial"
for the limiting case where one crystal gives only ONE pattern and
that's it, whether because of radiation damage or just the scanning
method being used.  There might be some rotation or oscillation of the
crystal during that time, but never measurements across more than one
detector frame [1].  Anything else is "just" an extreme case of
multi-crystal data acquisition.

I think this usage of the term comes from extending the definition "one
frame per crystal" to "one small wedge per crystal".  It sounds
innocuous, but as has already been mentioned the difference in data
processing between these two cases is absolutely enormous.

On top of that, there's the question of whether the exposures are
snapshots (stills) or have some rotation or oscillation.  This is why
many of my papers, e.g. the first CrystFEL paper [2], refer to "snapshot
serial crystallography" - I meant specifically both "one exposure per
crystal" AND "no rotation at all".

However, the term actually originated from some much earlier work in
the Spence group at ASU, which didn't involve crystals at all.  The
idea was to do the work of "crystallography" (i.e. determining
structures), but to put the molecules through the beam one by one
(serially) rather than side-by-side in a crystal (which I guess would
be "parallel crystallography"):
https://www.ncbi.nlm.nih.gov/pubmed/15169448
However, that technique didn't work out, and the term got co-opted for
the stuff we do nowadays.

It's also been commented that the days of getting an entire data set
(or anything close to it) from a single protein crystal may just be a
short period in the middle of crystallographic history, with
multi-crystal/serial techniques dominating in early work (pre 1990 ish)
and modern work.  Therefore, maybe before too long we'll be calling it
simply "crystallography" anyway.

Tom

[1] Ok, multiple frames per crystal might happen by accident, see for
example the last paragraph of section 3.2 of this paper:
http://journals.iucr.org/m/issues/2015/02/00/jt5008/index.html
However, this shouldn't be the point of the technique.

[2] http://scripts.iucr.org/cgi-bin/paper?S0021889812002312

[3] https://www.nature.com/articles/nature09750

-- 
Thomas White  
4E1F C14D 0E0A A014 FE5D 3FC6 C628 75D1 D4CA 4C30
Direct telephone: +49 (0)40 8998-5786



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Re: [ccp4bb] challenges in structural biology

[graeme.win...@diamond.ac.uk]

Dear All,

I have been enjoying “lurking” on this thread - some thoughts

I love this approach to conference organising :-) 

You missed radiation damage from this list ;-)  - is critically connected to 
isomorphism, resolution, serial methods and is probably the single greatest 
limitation on X-ray experiments. Also takes us back to the 80’s / 90’s - pre 
cryo - where many crystallographic studies were serial (and this was not 
special!) - we are just orders of magnitude faster today

Isomorphism, resolution, damage, serial methods, dynamic crystallography - 
these are all aspects of the same problem i.e. collection in an environment 
where the sample under study evolves - a topic of “moving targets” would seem 
to capture some of these ideas

I also echo Kay’s comment that serial _rotation_ crystallography is fine - we 
understand this and can easily get results which look OK / good according to 
traditional measures - when it comes to still shots from almost any source we 
are a long way behind

Back to lurking now

All best Graeme

> On 15 Jul 2019, at 20:44, Holton, James M 
> <270165b9f4cf-dmarc-requ...@jiscmail.ac.uk> wrote:
> 
> Hello folks,
> 
> I have the distinct honor of chairing the next Gordon Research 
> Conference on Diffraction Methods in Structural Biology (July 26-31 
> 2020).  This meeting will focus on the biggest challenges currently 
> faced by structural biologists, and I mean actual real-world 
> challenges.  As much as possible, these challenges will take the form of 
> friendly competitions with defined parameters, data, a scoring system, 
> and "winners", to be established along with other unpublished results 
> only at the meeting, as is tradition at GRCs.
> 
> But what are the principle challenges in biological structure 
> determination today?  I of course have my own ideas, but I feel like I'm 
> forgetting something.  Obvious choices are:
> 1) getting crystals to diffract better
> 2) building models into low-resolution maps (after failing at #1)
> 3) telling if a ligand is really there or not
> 4) the phase problem (dealing with weak signal, twinning and 
> pseudotranslation)
> 5) what does "resolution" really mean?
> 6) why are macromolecular R factors so much higher than small-molecule ones?
> 7) what is the best way to process serial crystallography data?
> 8) how should one deal with non-isomorphism in multi-crystal methods?
> 9) what is the "structure" of something that won't sit still?
> 
> What am I missing?  Is industry facing different problems than 
> academics?  Are there specific challenges facing electron-based 
> techniques?  If so, could the combined strength of all the world's 
> methods developers solve them?  I'm interested in hearing the voice of 
> this community.  On or off-list is fine.
> 
> -James Holton
> MAD Scientist
> 
> 
> 
> 
> To unsubscribe from the CCP4BB list, click the following link:
> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1


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Re: [ccp4bb] challenges in structural biology

Dear James (All),
I personally feel as if point 1
(crystallization) should be the main focus of discussion and future
developments. All other points are already constantly improving and people
are making constantly advances in those field (i.e., they seem to know how
to move things forward). Crystallization instead is desperately needing
for funding and new ideas. New technology, e.g., small arrays of
proteins/nanotechnology (1D or 2D crystals/scaffolds to inject in XFEL??),
new chemicals for crystallization, usage of smaller amounts of sample (10
+ 10 nl with acoustic dispenser ??), cheaper imaging hotels, or whatever
some clever people may come up with. Apologies if it may sound a bit too
obvious.
BW,
D
 
 
> Stating
the crystallography is dead might be a bit premature, it is still

> king for depositions.

>

>

>

> In 2017 we had a large number of fragment screening experiments
deposited.

>

>

>

>

>

>

>

>

From: CCP4 bulletin board  On Behalf Of
Nukri

> Sanishvili

> Sent: 15 July 2019 23:09

> To: CCP4BB@JISCMAIL.AC.UK

> Subject: Re: [ccp4bb] challenges in structural biology

>

>

>

> I know it is going to hijack the original topic but I could not
help...

>

>

>

> âThe reports of death of (macromolecular)
crystallography are greatly

> exaggerated.

>

> If we believed the prognosticators, it has been dead since the 80s
when

> some folks made the claim that the only relevant structures were
those

> solved by NMR.

>

> I think we've done quite well since then...

>

> Best,

>

> Nukri

>

>

>

> On Mon, Jul 15, 2019 at 3:45 PM  <mailto:r...@mrc-lmb.cam.ac.uk> > wrote:

>

> Hi Tassos, Tim,

>

> I wonder why would you or anyone on this list worry whether
biological

> questions that can be asked and answered with structures are relevant
to

> justify the resources? I think there is abundant evidence that this
is the

> case. Unless your point is that crystallography is now dead for
all

> practical

> purposes... then yes, I fully agree :-) It would however be wrong to
erase

> its

> historical contribution to understanding biology.

>

> Best wishes,

>

> Radu

>

>

>> I would wonder more if the biological questions you can *ask*
with a

>> (crystal)

>> structure are sufficiently relevant to justify the resources.

>>

>> Sent from my iPhone

>>

>>> On 15 Jul 2019, at 22:08, Tim Grüne
>> <mailto:tim.gru...@univie.ac.at> > wrote:

>>>

>>> Dear James,

>>>

>>> 10) are the biological questions that you can answer with a
(crystal)

>>> structure sufficiently relevant to justify the resources?

>>>

>>> Best,

>>> Tim

>>>

>>>

>>>

>>> Am 15.07.2019 21:44, schrieb Holton, James M:

>>>> Hello folks,

>>>> I have the distinct honor of chairing the next Gordon
Research

>>>> Conference on Diffraction Methods in Structural Biology
(July 26-31

>>>> 2020). This meeting will focus on the biggest challenges
currently

>>>> faced by structural biologists, and I mean actual
real-world

>>>> challenges. As much as possible, these challenges will
take the form

>>>> of

>>>> friendly competitions with defined parameters, data, a
scoring system,

>>>> and "winners", to be established along with
other unpublished results

>>>> only at the meeting, as is tradition at GRCs.

>>>> But what are the principle challenges in biological
structure

>>>> determination today? I of course have my own ideas, but I
feel like

>>>> I'm

>>>> forgetting something. Obvious choices are:

>>>> 1) getting crystals to diffract better

>>>> 2) building models into low-resolution maps (after
failing at #1)

>>>> 3) telling if a ligand is really there or not

>>>> 4) the phase problem (dealing with weak signal, twinning
and

>>>> pseudotranslation)

>>>> 5) what does "resolution" really mean?

>>>> 6) why are macromolecular R factors so much higher than
small-molecule

>>>> ones?

>>>> 7) what is the best way to process serial crystallography
data?

>>>> 8) how should one deal with non-isomorphism in
multi-crystal methods?

>>>> 9) what is the "structure" of something that
won't sit still?

>>>> What am I missing? Is industry facing different problems
than

>>>> academics? Are there specific challenges facing
electron-based

>>>> t

Re: [ccp4bb] challenges in structural biology

[radu]

Hi Both,

I am not questioning the PDB stats, the issue was whether (crystal) structures
are sufficiently relevant to address biological questions and justify the
resources. Fragment screening is one example where investment in protein
crystallography can still be justified (for now). But it doesn't really ask or
answer biological questions... for these, whether we like it or not,
macromolecular crystallography (or NMR, even in cell) cannot be the future. In
my opinion :-)

Best wishes,

Radu


> Stating the crystallography is dead might be a bit premature, it is still king
> for depositions.
>
>
>
> In 2017 we had a large number of fragment screening experiments deposited.
>
>
>
>
>
>
>
> From: CCP4 bulletin board  On Behalf Of Nukri
> Sanishvili
> Sent: 15 July 2019 23:09
> To: CCP4BB@JISCMAIL.AC.UK
> Subject: Re: [ccp4bb] challenges in structural biology
>
>
>
> I know it is going to hijack the original topic but I could not help...
>
>
>
> “The reports of death of (macromolecular) crystallography are greatly
> exaggerated.
>
> If we believed the prognosticators, it has been dead since the 80s when some
> folks made the claim that the only relevant structures were those solved by
> NMR.
>
> I think we've done quite well since then...
>
> Best,
>
> Nukri
>
>
>
> On Mon, Jul 15, 2019 at 3:45 PM  <mailto:r...@mrc-lmb.cam.ac.uk> > wrote:
>
> Hi Tassos, Tim,
>
> I wonder why would you or anyone on this list worry whether biological
> questions that can be asked and answered with structures are relevant to
> justify the resources? I think there is abundant evidence that this is the
> case. Unless your point is that crystallography is now dead for all practical
> purposes... then yes, I fully agree :-) It would however be wrong to erase its
> historical contribution to understanding biology.
>
> Best wishes,
>
> Radu
>
>
>> I would wonder more if the biological questions you can *ask* with a
>> (crystal)
>> structure are sufficiently relevant to justify the resources.
>>
>> Sent from my iPhone
>>
>>> On 15 Jul 2019, at 22:08, Tim Grüne >> <mailto:tim.gru...@univie.ac.at> > wrote:
>>>
>>> Dear James,
>>>
>>> 10) are the biological questions that you can answer with a (crystal)
>>> structure sufficiently relevant to justify the resources?
>>>
>>> Best,
>>> Tim
>>>
>>>
>>>
>>> Am 15.07.2019 21:44, schrieb Holton, James M:
>>>> Hello folks,
>>>> I have the distinct honor of chairing the next Gordon Research
>>>> Conference on Diffraction Methods in Structural Biology (July 26-31
>>>> 2020).  This meeting will focus on the biggest challenges currently
>>>> faced by structural biologists, and I mean actual real-world
>>>> challenges.  As much as possible, these challenges will take the form of
>>>> friendly competitions with defined parameters, data, a scoring system,
>>>> and "winners", to be established along with other unpublished results
>>>> only at the meeting, as is tradition at GRCs.
>>>> But what are the principle challenges in biological structure
>>>> determination today?  I of course have my own ideas, but I feel like I'm
>>>> forgetting something.  Obvious choices are:
>>>> 1) getting crystals to diffract better
>>>> 2) building models into low-resolution maps (after failing at #1)
>>>> 3) telling if a ligand is really there or not
>>>> 4) the phase problem (dealing with weak signal, twinning and
>>>> pseudotranslation)
>>>> 5) what does "resolution" really mean?
>>>> 6) why are macromolecular R factors so much higher than small-molecule
>>>> ones?
>>>> 7) what is the best way to process serial crystallography data?
>>>> 8) how should one deal with non-isomorphism in multi-crystal methods?
>>>> 9) what is the "structure" of something that won't sit still?
>>>> What am I missing?  Is industry facing different problems than
>>>> academics?  Are there specific challenges facing electron-based
>>>> techniques?  If so, could the combined strength of all the world's
>>>> methods developers solve them?  I'm interested in hearing the voice of
>>>> this community.  On or off-list is fine.
>>>> -James Holton
>>>> MAD Scientist
>>>> 
>>>> To unsubscribe from the CCP4BB list, click t

Re: [ccp4bb] challenges in structural biology

[John Berrisford]

Stating the crystallography is dead might be a bit premature, it is still king 
for depositions.

 

In 2017 we had a large number of fragment screening experiments deposited.

 



 

From: CCP4 bulletin board  On Behalf Of Nukri Sanishvili
Sent: 15 July 2019 23:09
To: CCP4BB@JISCMAIL.AC.UK
Subject: Re: [ccp4bb] challenges in structural biology

 

I know it is going to hijack the original topic but I could not help...

 

“The reports of death of (macromolecular) crystallography are greatly 
exaggerated.

If we believed the prognosticators, it has been dead since the 80s when some 
folks made the claim that the only relevant structures were those solved by NMR.

I think we've done quite well since then...

Best,

Nukri

 

On Mon, Jul 15, 2019 at 3:45 PM mailto:r...@mrc-lmb.cam.ac.uk> > wrote:

Hi Tassos, Tim,

I wonder why would you or anyone on this list worry whether biological
questions that can be asked and answered with structures are relevant to
justify the resources? I think there is abundant evidence that this is the
case. Unless your point is that crystallography is now dead for all practical
purposes... then yes, I fully agree :-) It would however be wrong to erase its
historical contribution to understanding biology.

Best wishes,

Radu


> I would wonder more if the biological questions you can *ask* with a (crystal)
> structure are sufficiently relevant to justify the resources.
>
> Sent from my iPhone
>
>> On 15 Jul 2019, at 22:08, Tim Grüne > <mailto:tim.gru...@univie.ac.at> > wrote:
>>
>> Dear James,
>>
>> 10) are the biological questions that you can answer with a (crystal)
>> structure sufficiently relevant to justify the resources?
>>
>> Best,
>> Tim
>>
>>
>>
>> Am 15.07.2019 21:44, schrieb Holton, James M:
>>> Hello folks,
>>> I have the distinct honor of chairing the next Gordon Research
>>> Conference on Diffraction Methods in Structural Biology (July 26-31
>>> 2020).  This meeting will focus on the biggest challenges currently
>>> faced by structural biologists, and I mean actual real-world
>>> challenges.  As much as possible, these challenges will take the form of
>>> friendly competitions with defined parameters, data, a scoring system,
>>> and "winners", to be established along with other unpublished results
>>> only at the meeting, as is tradition at GRCs.
>>> But what are the principle challenges in biological structure
>>> determination today?  I of course have my own ideas, but I feel like I'm
>>> forgetting something.  Obvious choices are:
>>> 1) getting crystals to diffract better
>>> 2) building models into low-resolution maps (after failing at #1)
>>> 3) telling if a ligand is really there or not
>>> 4) the phase problem (dealing with weak signal, twinning and
>>> pseudotranslation)
>>> 5) what does "resolution" really mean?
>>> 6) why are macromolecular R factors so much higher than small-molecule
>>> ones?
>>> 7) what is the best way to process serial crystallography data?
>>> 8) how should one deal with non-isomorphism in multi-crystal methods?
>>> 9) what is the "structure" of something that won't sit still?
>>> What am I missing?  Is industry facing different problems than
>>> academics?  Are there specific challenges facing electron-based
>>> techniques?  If so, could the combined strength of all the world's
>>> methods developers solve them?  I'm interested in hearing the voice of
>>> this community.  On or off-list is fine.
>>> -James Holton
>>> MAD Scientist
>>> 
>>> To unsubscribe from the CCP4BB list, click the following link:
>>> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB 
>>> <https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1> =1
>>
>> --
>> --
>> Tim Gruene
>> Head of the Centre for X-ray Structure Analysis
>> Faculty of Chemistry
>> University of Vienna
>>
>> Phone: +43-1-4277-70202
>>
>> GPG Key ID = A46BEE1A
>>
>> 
>>
>> To unsubscribe from the CCP4BB list, click the following link:
>> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB 
>> <https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1> =1
>
> 
>
> To unsubscribe from the CCP4BB list, click the following link:
> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB 
&

Re: [ccp4bb] challenges in structural biology

[selina.st...@diamond.ac.uk]

Hi all,

following up on Kay's point, I think it might be worth to discuss what we as a 
community understand by serial crystallography and what makes it
different from multiple crystal crystallography. I recently gave a talk about 
multiple-crystal and serial crystallography at a course and I could not 
find any textbook definition. Kay's email suggests that my understanding 
differs from his...

Best regards,

Selina



On 16/07/2019, 12:04, "CCP4 bulletin board on behalf of Kay Diederichs" 
 wrote:

Hello James,

I like your list, but I wonder how much of this can be covered in 
meaningful depth during a single GRC.

Your item
>7) what is the best way to process serial crystallography data?
deserves differentiation; there is a huge gap between serial synchrotron 
crystallography (SSX) with rotation of a few degrees, and serial femtosecond 
crystallography (SFX) at X-FELs. And stills collected at a synchrotron has 
aspects of both techniques.

best,
Kay


On Mon, 15 Jul 2019 19:44:03 +, Holton, James M 
 wrote:

>Hello folks,
>
>I have the distinct honor of chairing the next Gordon Research 
>Conference on Diffraction Methods in Structural Biology (July 26-31 
>2020).  This meeting will focus on the biggest challenges currently 
>faced by structural biologists, and I mean actual real-world 
>challenges.  As much as possible, these challenges will take the form of 
>friendly competitions with defined parameters, data, a scoring system, 
>and "winners", to be established along with other unpublished results 
>only at the meeting, as is tradition at GRCs.
>
>But what are the principle challenges in biological structure 
>determination today?  I of course have my own ideas, but I feel like I'm 
>forgetting something.  Obvious choices are:
>1) getting crystals to diffract better
>2) building models into low-resolution maps (after failing at #1)
>3) telling if a ligand is really there or not
>4) the phase problem (dealing with weak signal, twinning and 
>pseudotranslation)
>5) what does "resolution" really mean?
>6) why are macromolecular R factors so much higher than small-molecule 
ones?
>7) what is the best way to process serial crystallography data?
>8) how should one deal with non-isomorphism in multi-crystal methods?
>9) what is the "structure" of something that won't sit still?
>
>What am I missing?  Is industry facing different problems than 
>academics?  Are there specific challenges facing electron-based 
>techniques?  If so, could the combined strength of all the world's 
>methods developers solve them?  I'm interested in hearing the voice of 
>this community.  On or off-list is fine.
>
>-James Holton
>MAD Scientist
>
>
>
>
>To unsubscribe from the CCP4BB list, click the following link:
>https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1



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please notify us of receipt by returning the e-mail and do not use, copy, 
retain, distribute or disclose the information in or attached to the e-mail.
Any opinions expressed within this e-mail are those of the individual and not 
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Diamond Light Source Ltd. cannot guarantee that this e-mail or any attachments 
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may sustain as a result of software viruses which may be transmitted in or with 
the message.
Diamond Light Source Limited (company no. 4375679). Registered in England and 
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Re: [ccp4bb] challenges in structural biology

[Kay Diederichs]

Hello James,

I like your list, but I wonder how much of this can be covered in meaningful 
depth during a single GRC.

Your item
>7) what is the best way to process serial crystallography data?
deserves differentiation; there is a huge gap between serial synchrotron 
crystallography (SSX) with rotation of a few degrees, and serial femtosecond 
crystallography (SFX) at X-FELs. And stills collected at a synchrotron has 
aspects of both techniques.

best,
Kay


On Mon, 15 Jul 2019 19:44:03 +, Holton, James M 
 wrote:

>Hello folks,
>
>I have the distinct honor of chairing the next Gordon Research 
>Conference on Diffraction Methods in Structural Biology (July 26-31 
>2020).  This meeting will focus on the biggest challenges currently 
>faced by structural biologists, and I mean actual real-world 
>challenges.  As much as possible, these challenges will take the form of 
>friendly competitions with defined parameters, data, a scoring system, 
>and "winners", to be established along with other unpublished results 
>only at the meeting, as is tradition at GRCs.
>
>But what are the principle challenges in biological structure 
>determination today?  I of course have my own ideas, but I feel like I'm 
>forgetting something.  Obvious choices are:
>1) getting crystals to diffract better
>2) building models into low-resolution maps (after failing at #1)
>3) telling if a ligand is really there or not
>4) the phase problem (dealing with weak signal, twinning and 
>pseudotranslation)
>5) what does "resolution" really mean?
>6) why are macromolecular R factors so much higher than small-molecule ones?
>7) what is the best way to process serial crystallography data?
>8) how should one deal with non-isomorphism in multi-crystal methods?
>9) what is the "structure" of something that won't sit still?
>
>What am I missing?  Is industry facing different problems than 
>academics?  Are there specific challenges facing electron-based 
>techniques?  If so, could the combined strength of all the world's 
>methods developers solve them?  I'm interested in hearing the voice of 
>this community.  On or off-list is fine.
>
>-James Holton
>MAD Scientist
>
>
>
>
>To unsubscribe from the CCP4BB list, click the following link:
>https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1



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Re: [ccp4bb] challenges in structural biology

[vincent Chaptal]

Hi James,

what about the use of highly anisotropic data, what it means in terms of 
macromolecule arrangement within the crystal, and how to use the data 
appropriately? An obvious link to item 5) and what resolution is in such 
case?
An opening to item 6) and contribution of solvent as anisotropy is 
especially enhanced in membrane protein crystals... what would be the 
implication of the solvent and how to account for it?


All the best
Vincent

Le 15/07/2019 à 21:44, Holton, James M a écrit :

Hello folks,

I have the distinct honor of chairing the next Gordon Research
Conference on Diffraction Methods in Structural Biology (July 26-31
2020).  This meeting will focus on the biggest challenges currently
faced by structural biologists, and I mean actual real-world
challenges.  As much as possible, these challenges will take the form of
friendly competitions with defined parameters, data, a scoring system,
and "winners", to be established along with other unpublished results
only at the meeting, as is tradition at GRCs.

But what are the principle challenges in biological structure
determination today?  I of course have my own ideas, but I feel like I'm
forgetting something.  Obvious choices are:
1) getting crystals to diffract better
2) building models into low-resolution maps (after failing at #1)
3) telling if a ligand is really there or not
4) the phase problem (dealing with weak signal, twinning and
pseudotranslation)
5) what does "resolution" really mean?
6) why are macromolecular R factors so much higher than small-molecule ones?
7) what is the best way to process serial crystallography data?
8) how should one deal with non-isomorphism in multi-crystal methods?
9) what is the "structure" of something that won't sit still?

What am I missing?  Is industry facing different problems than
academics?  Are there specific challenges facing electron-based
techniques?  If so, could the combined strength of all the world's
methods developers solve them?  I'm interested in hearing the voice of
this community.  On or off-list is fine.

-James Holton
MAD Scientist




To unsubscribe from the CCP4BB list, click the following link:
https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1


--

Vincent Chaptal, PhD

MMSB -UMR5086

Drug Resistance and Membrane Proteins Laboratory

7 passage du Vercors

69007 LYON

FRANCE

+33 4 37 65 29 01

http://mmsb.cnrs.fr/en/





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Re: [ccp4bb] challenges in structural biology

[Barone, Matthias]

Something that pops up here routinely, connected to 5) what does "resolution" 
really mean?:

While new methods are being implemented to improve the accuracy of models or to 
deal with weak data, how to convince editors to accept the new methods?

cheers, matthias





Dr. Matthias Barone

AG Kuehne, Rational Drug Design

Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
Robert-Rössle-Strasse 10
13125 Berlin

Germany
Phone: +49 (0)30 94793-284


From: CCP4 bulletin board  on behalf of Frank Von Delft 

Sent: Tuesday, July 16, 2019 6:34:16 AM
To: CCP4BB@JISCMAIL.AC.UK
Subject: Re: [ccp4bb] challenges in structural biology

1.1  Getting many diverse conformations routinely into well-diffracting
crystals;  and knowing how to interpret them biologically.

On 15/07/2019 20:44, Holton, James M wrote:
> Hello folks,
>
> I have the distinct honor of chairing the next Gordon Research
> Conference on Diffraction Methods in Structural Biology (July 26-31
> 2020).  This meeting will focus on the biggest challenges currently
> faced by structural biologists, and I mean actual real-world
> challenges.  As much as possible, these challenges will take the form of
> friendly competitions with defined parameters, data, a scoring system,
> and "winners", to be established along with other unpublished results
> only at the meeting, as is tradition at GRCs.
>
> But what are the principle challenges in biological structure
> determination today?  I of course have my own ideas, but I feel like I'm
> forgetting something.  Obvious choices are:
> 1) getting crystals to diffract better
> 2) building models into low-resolution maps (after failing at #1)
> 3) telling if a ligand is really there or not
> 4) the phase problem (dealing with weak signal, twinning and
> pseudotranslation)
> 5) what does "resolution" really mean?
> 6) why are macromolecular R factors so much higher than small-molecule ones?
> 7) what is the best way to process serial crystallography data?
> 8) how should one deal with non-isomorphism in multi-crystal methods?
> 9) what is the "structure" of something that won't sit still?
>
> What am I missing?  Is industry facing different problems than
> academics?  Are there specific challenges facing electron-based
> techniques?  If so, could the combined strength of all the world's
> methods developers solve them?  I'm interested in hearing the voice of
> this community.  On or off-list is fine.
>
> -James Holton
> MAD Scientist
>
>
> 
>
> To unsubscribe from the CCP4BB list, click the following link:
> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1





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Re: [ccp4bb] challenges in structural biology

[Frank Von Delft]

1.1  Getting many diverse conformations routinely into well-diffracting 
crystals;  and knowing how to interpret them biologically.

On 15/07/2019 20:44, Holton, James M wrote:
> Hello folks,
>
> I have the distinct honor of chairing the next Gordon Research
> Conference on Diffraction Methods in Structural Biology (July 26-31
> 2020).  This meeting will focus on the biggest challenges currently
> faced by structural biologists, and I mean actual real-world
> challenges.  As much as possible, these challenges will take the form of
> friendly competitions with defined parameters, data, a scoring system,
> and "winners", to be established along with other unpublished results
> only at the meeting, as is tradition at GRCs.
>
> But what are the principle challenges in biological structure
> determination today?  I of course have my own ideas, but I feel like I'm
> forgetting something.  Obvious choices are:
> 1) getting crystals to diffract better
> 2) building models into low-resolution maps (after failing at #1)
> 3) telling if a ligand is really there or not
> 4) the phase problem (dealing with weak signal, twinning and
> pseudotranslation)
> 5) what does "resolution" really mean?
> 6) why are macromolecular R factors so much higher than small-molecule ones?
> 7) what is the best way to process serial crystallography data?
> 8) how should one deal with non-isomorphism in multi-crystal methods?
> 9) what is the "structure" of something that won't sit still?
>
> What am I missing?  Is industry facing different problems than
> academics?  Are there specific challenges facing electron-based
> techniques?  If so, could the combined strength of all the world's
> methods developers solve them?  I'm interested in hearing the voice of
> this community.  On or off-list is fine.
>
> -James Holton
> MAD Scientist
>
>
> 
>
> To unsubscribe from the CCP4BB list, click the following link:
> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1





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Re: [ccp4bb] challenges in structural biology

[Keller, Jacob]

I like both of these points! I would comment/add the following:

1) What are the tools we can use for metals in structural biology? Note, I am 
biased here.

-Including validation of solute ions like Na/K/Cl etc
-Some metric of identity confidence?

2) Micro electron diffraction methods - ability to use on small crystals (which 
speaks to Tom's point) and a potential bridge between cryo-EM and X-ray 
diffraction techniques?

-What about an XFEL equivalent for electrons with their greater scattering? I 
looked into this a while back, and there seemed to be some pretty tough things 
about it, but is there hope? Maybe any purifiable protein could be solved in 
this way? Would it have to be done by diffraction, or could focusing work 
somehow?

JPK




Sarah EJ Bowman, PhD

Associate Research Scientist, Hauptman-Woodward Medical Research Institute 
Director, High-Throughput Crystallization Screening Center

https://urldefense.proofpoint.com/v2/url?u=http-3A__www.getacrystal.org=DwIF-g=LU6cRtx0xgB8s29tIz9Olw=eLCg9eJ4Rs_LnxfUWsp7FSxhIEcZYmTSU4Uyq1bRYPI=HLRpGMGxTyZSjqW-aeakIElqVXKo3CvO_O36dUmNgKY=7uXULBobMzHYWnHc-YO4fFjHH7PbGQXufIRarsr4dQE=
 

sbow...@hwi.buffalo.edu


From: CCP4 bulletin board  on behalf of Peat, Tom 
(Manufacturing, Parkville) 
Sent: Monday, July 15, 2019 8:07 PM
To: CCP4BB@JISCMAIL.AC.UK
Subject: Re: challenges in structural biology

Hello Tim,

I'm not sure this question is specific to crystallography- I believe the same 
can be asked of any experiment in any field?
And if one wants to get into true costs- was it worth it to build the Large 
Hadron Collider to statistically prove that the Higgs boson exists?
I'm guessing it was worth it to the folks that got their name on the paper...
Cheers, tom

-Original Message-
From: CCP4 bulletin board [mailto:CCP4BB@JISCMAIL.AC.UK] On Behalf Of Tim Grüne
Sent: Tuesday, 16 July 2019 6:09 AM
To: CCP4BB@JISCMAIL.AC.UK
Subject: Re: [ccp4bb] challenges in structural biology

Dear James,

10) are the biological questions that you can answer with a (crystal) structure 
sufficiently relevant to justify the resources?

Best,
Tim



Am 15.07.2019 21:44, schrieb Holton, James M:
> Hello folks,
>
> I have the distinct honor of chairing the next Gordon Research 
> Conference on Diffraction Methods in Structural Biology (July 26-31 
> 2020).  This meeting will focus on the biggest challenges currently 
> faced by structural biologists, and I mean actual real-world 
> challenges.  As much as possible, these challenges will take the form 
> of friendly competitions with defined parameters, data, a scoring 
> system, and "winners", to be established along with other unpublished 
> results only at the meeting, as is tradition at GRCs.
>
> But what are the principle challenges in biological structure 
> determination today?  I of course have my own ideas, but I feel like 
> I'm forgetting something.  Obvious choices are:
> 1) getting crystals to diffract better
> 2) building models into low-resolution maps (after failing at #1)
> 3) telling if a ligand is really there or not
> 4) the phase problem (dealing with weak signal, twinning and
> pseudotranslation)
> 5) what does "resolution" really mean?
> 6) why are macromolecular R factors so much higher than small-molecule 
> ones?
> 7) what is the best way to process serial crystallography data?
> 8) how should one deal with non-isomorphism in multi-crystal methods?
> 9) what is the "structure" of something that won't sit still?
>
> What am I missing?  Is industry facing different problems than 
> academics?  Are there specific challenges facing electron-based 
> techniques?  If so, could the combined strength of all the world's 
> methods developers solve them?  I'm interested in hearing the voice of 
> this community.  On or off-list is fine.
>
> -James Holton
> MAD Scientist
>
>
> ##
> ##
>
> To unsubscribe from the CCP4BB list, click the following link:
> https://urldefense.proofpoint.com/v2/url?u=https-3A__www.jiscmail.ac.u
> k_cgi-2Dbin_webadmin-3FSUBED1-3DCCP4BB-26A-3D1=DwIF-g=LU6cRtx0xgB8
> s29tIz9Olw=eLCg9eJ4Rs_LnxfUWsp7FSxhIEcZYmTSU4Uyq1bRYPI=HLRpGMGxTyZ
> SjqW-aeakIElqVXKo3CvO_O36dUmNgKY=Q23TMeWBhuH2_xEAYk3-wjMz65NwxYH-I3E
> fSr0dcAs=

--
--
Tim Gruene
Head of the Centre for X-ray Structure Analysis Faculty of Chemistry University 
of Vienna

Phone: +43-1-4277-70202

GPG Key ID = A46BEE1A



To unsubscribe from the CCP4BB list, click the following link:
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Re: [ccp4bb] challenges in structural biology

[Sarah Bowman]

Hi James,

2 things come to mind.

1) What are the tools we can use for metals in structural biology? Note, I am 
biased here…

2) Micro electron diffraction methods - ability to use on small crystals (which 
speaks to Tom’s point) and a potential bridge between cryo-EM and X-ray 
diffraction techniques?

Awesome that you are asking for community engagement on this!
Cheers,
Sarah


Sarah EJ Bowman, PhD

Associate Research Scientist, Hauptman-Woodward Medical Research Institute
Director, High-Throughput Crystallization Screening Center

www.getacrystal.org

sbow...@hwi.buffalo.edu


From: CCP4 bulletin board  on behalf of Peat, Tom 
(Manufacturing, Parkville) 
Sent: Monday, July 15, 2019 8:07 PM
To: CCP4BB@JISCMAIL.AC.UK
Subject: Re: challenges in structural biology

Hello Tim,

I'm not sure this question is specific to crystallography- I believe the same 
can be asked of any experiment in any field?
And if one wants to get into true costs- was it worth it to build the Large 
Hadron Collider to statistically prove that the Higgs boson exists?
I'm guessing it was worth it to the folks that got their name on the paper...
Cheers, tom

-Original Message-
From: CCP4 bulletin board [mailto:CCP4BB@JISCMAIL.AC.UK] On Behalf Of Tim Grüne
Sent: Tuesday, 16 July 2019 6:09 AM
To: CCP4BB@JISCMAIL.AC.UK
Subject: Re: [ccp4bb] challenges in structural biology

Dear James,

10) are the biological questions that you can answer with a (crystal) structure 
sufficiently relevant to justify the resources?

Best,
Tim



Am 15.07.2019 21:44, schrieb Holton, James M:
> Hello folks,
>
> I have the distinct honor of chairing the next Gordon Research
> Conference on Diffraction Methods in Structural Biology (July 26-31
> 2020).  This meeting will focus on the biggest challenges currently
> faced by structural biologists, and I mean actual real-world
> challenges.  As much as possible, these challenges will take the form
> of friendly competitions with defined parameters, data, a scoring
> system, and "winners", to be established along with other unpublished
> results only at the meeting, as is tradition at GRCs.
>
> But what are the principle challenges in biological structure
> determination today?  I of course have my own ideas, but I feel like
> I'm forgetting something.  Obvious choices are:
> 1) getting crystals to diffract better
> 2) building models into low-resolution maps (after failing at #1)
> 3) telling if a ligand is really there or not
> 4) the phase problem (dealing with weak signal, twinning and
> pseudotranslation)
> 5) what does "resolution" really mean?
> 6) why are macromolecular R factors so much higher than small-molecule
> ones?
> 7) what is the best way to process serial crystallography data?
> 8) how should one deal with non-isomorphism in multi-crystal methods?
> 9) what is the "structure" of something that won't sit still?
>
> What am I missing?  Is industry facing different problems than
> academics?  Are there specific challenges facing electron-based
> techniques?  If so, could the combined strength of all the world's
> methods developers solve them?  I'm interested in hearing the voice of
> this community.  On or off-list is fine.
>
> -James Holton
> MAD Scientist
>
>
> ##
> ##
>
> To unsubscribe from the CCP4BB list, click the following link:
> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1

--
--
Tim Gruene
Head of the Centre for X-ray Structure Analysis Faculty of Chemistry University 
of Vienna

Phone: +43-1-4277-70202

GPG Key ID = A46BEE1A



To unsubscribe from the CCP4BB list, click the following link:
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Re: [ccp4bb] challenges in structural biology

[Peat, Tom (Manufacturing, Parkville)]

Hello Tim, 

I'm not sure this question is specific to crystallography- I believe the same 
can be asked of any experiment in any field? 
And if one wants to get into true costs- was it worth it to build the Large 
Hadron Collider to statistically prove that the Higgs boson exists? 
I'm guessing it was worth it to the folks that got their name on the paper... 
Cheers, tom 

-Original Message-
From: CCP4 bulletin board [mailto:CCP4BB@JISCMAIL.AC.UK] On Behalf Of Tim Grüne
Sent: Tuesday, 16 July 2019 6:09 AM
To: CCP4BB@JISCMAIL.AC.UK
Subject: Re: [ccp4bb] challenges in structural biology

Dear James,

10) are the biological questions that you can answer with a (crystal) structure 
sufficiently relevant to justify the resources?

Best,
Tim



Am 15.07.2019 21:44, schrieb Holton, James M:
> Hello folks,
> 
> I have the distinct honor of chairing the next Gordon Research 
> Conference on Diffraction Methods in Structural Biology (July 26-31 
> 2020).  This meeting will focus on the biggest challenges currently 
> faced by structural biologists, and I mean actual real-world 
> challenges.  As much as possible, these challenges will take the form 
> of friendly competitions with defined parameters, data, a scoring 
> system, and "winners", to be established along with other unpublished 
> results only at the meeting, as is tradition at GRCs.
> 
> But what are the principle challenges in biological structure 
> determination today?  I of course have my own ideas, but I feel like 
> I'm forgetting something.  Obvious choices are:
> 1) getting crystals to diffract better
> 2) building models into low-resolution maps (after failing at #1)
> 3) telling if a ligand is really there or not
> 4) the phase problem (dealing with weak signal, twinning and
> pseudotranslation)
> 5) what does "resolution" really mean?
> 6) why are macromolecular R factors so much higher than small-molecule 
> ones?
> 7) what is the best way to process serial crystallography data?
> 8) how should one deal with non-isomorphism in multi-crystal methods?
> 9) what is the "structure" of something that won't sit still?
> 
> What am I missing?  Is industry facing different problems than 
> academics?  Are there specific challenges facing electron-based 
> techniques?  If so, could the combined strength of all the world's 
> methods developers solve them?  I'm interested in hearing the voice of 
> this community.  On or off-list is fine.
> 
> -James Holton
> MAD Scientist
> 
> 
> ##
> ##
> 
> To unsubscribe from the CCP4BB list, click the following link:
> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1

--
--
Tim Gruene
Head of the Centre for X-ray Structure Analysis Faculty of Chemistry University 
of Vienna

Phone: +43-1-4277-70202

GPG Key ID = A46BEE1A



To unsubscribe from the CCP4BB list, click the following link:
https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1



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Re: [ccp4bb] challenges in structural biology

[Peat, Tom (Manufacturing, Parkville)]

If one were able to crystallise almost all proteins (and complexes) reliably 
and with good diffraction, that would make most people's lives much easier. So 
I would go with 1) as a grand challenge.

Many of the rest follow on from not having 'good' crystals to start with.

cheers, tom


Tom Peat
Proteins Group
Biomedical Program, CSIRO
343 Royal Parade
Parkville, VIC, 3052
+613 9662 7304
+614 57 539 419
tom.p...@csiro.au



From: CCP4 bulletin board  on behalf of Holton, James M 
<270165b9f4cf-dmarc-requ...@jiscmail.ac.uk>
Sent: Tuesday, July 16, 2019 5:44 AM
To: CCP4BB@JISCMAIL.AC.UK
Subject: [ccp4bb] challenges in structural biology

Hello folks,

I have the distinct honor of chairing the next Gordon Research
Conference on Diffraction Methods in Structural Biology (July 26-31
2020).  This meeting will focus on the biggest challenges currently
faced by structural biologists, and I mean actual real-world
challenges.  As much as possible, these challenges will take the form of
friendly competitions with defined parameters, data, a scoring system,
and "winners", to be established along with other unpublished results
only at the meeting, as is tradition at GRCs.

But what are the principle challenges in biological structure
determination today?  I of course have my own ideas, but I feel like I'm
forgetting something.  Obvious choices are:
1) getting crystals to diffract better
2) building models into low-resolution maps (after failing at #1)
3) telling if a ligand is really there or not
4) the phase problem (dealing with weak signal, twinning and
pseudotranslation)
5) what does "resolution" really mean?
6) why are macromolecular R factors so much higher than small-molecule ones?
7) what is the best way to process serial crystallography data?
8) how should one deal with non-isomorphism in multi-crystal methods?
9) what is the "structure" of something that won't sit still?

What am I missing?  Is industry facing different problems than
academics?  Are there specific challenges facing electron-based
techniques?  If so, could the combined strength of all the world's
methods developers solve them?  I'm interested in hearing the voice of
this community.  On or off-list is fine.

-James Holton
MAD Scientist




To unsubscribe from the CCP4BB list, click the following link:
https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1



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Re: [ccp4bb] challenges in structural biology

[Minmin Yu]

Hi James, 
7) or 8) What are a few different collection methods
including at RT for serial crystallography data?
Temperature vs global and site-specific radiation damage  ---
RT serial crystallography
            Temperature vs multiple
conformers 
 
Thanks,
Minmin
 
> Dear James,

>

> 10) are the biological questions that you can answer with a
(crystal)

> structure sufficiently relevant to justify the resources?

>

> Best,

> Tim

>

>

>

> Am 15.07.2019 21:44, schrieb Holton, James M:

>> Hello folks,

>>

>> I have the distinct honor of chairing the next Gordon Research

>> Conference on Diffraction Methods in Structural Biology (July
26-31

>> 2020).  This meeting will focus on the biggest
challenges currently

>> faced by structural biologists, and I mean actual real-world

>> challenges.  As much as possible, these challenges
will take the form

>> of

>> friendly competitions with defined parameters, data, a scoring
system,

>> and "winners", to be established along with other
unpublished results

>> only at the meeting, as is tradition at GRCs.

>>

>> But what are the principle challenges in biological structure

>> determination today?  I of course have my own ideas,
but I feel like

>> I'm

>> forgetting something.  Obvious choices are:

>> 1) getting crystals to diffract better

>> 2) building models into low-resolution maps (after failing at
#1)

>> 3) telling if a ligand is really there or not

>> 4) the phase problem (dealing with weak signal, twinning and

>> pseudotranslation)

>> 5) what does "resolution" really mean?

>> 6) why are macromolecular R factors so much higher than
small-molecule

>> ones?

>> 7) what is the best way to process serial crystallography
data?

>> 8) how should one deal with non-isomorphism in multi-crystal
methods?

>> 9) what is the "structure" of something that won't sit
still?

>>

>> What am I missing?  Is industry facing different
problems than

>> academics?  Are there specific challenges facing
electron-based

>> techniques?  If so, could the combined strength of
all the world's

>> methods developers solve them?  I'm interested in
hearing the voice of

>> this community.  On or off-list is fine.

>>

>> -James Holton

>> MAD Scientist

>>

>>

>>


>>

>> To unsubscribe from the CCP4BB list, click the following link:

>>
https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1

>

> --

> --

> Tim Gruene

> Head of the Centre for X-ray Structure Analysis

> Faculty of Chemistry

> University of Vienna

>

> Phone: +43-1-4277-70202

>

> GPG Key ID = A46BEE1A

>

>


>

> To unsubscribe from the CCP4BB list, click the following link:

> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1

>



To unsubscribe from the CCP4BB list, click the following link:
https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1

Re: [ccp4bb] challenges in structural biology

[Minmin Yu]

Hi James, 
7) or 8) What are a few different collection methods
including at RT for serial crystallography data?
Temperature vs global and site-specific radiation damage  ---
RT serial crystallography
            Temperature vs multiple
conformers 
 
Thanks,
Minmin
 
> Dear James,

>

> 10) are the biological questions that you can answer with a
(crystal)

> structure sufficiently relevant to justify the resources?

>

> Best,

> Tim

>

>

>

> Am 15.07.2019 21:44, schrieb Holton, James M:

>> Hello folks,

>>

>> I have the distinct honor of chairing the next Gordon Research

>> Conference on Diffraction Methods in Structural Biology (July
26-31

>> 2020).  This meeting will focus on the biggest
challenges currently

>> faced by structural biologists, and I mean actual real-world

>> challenges.  As much as possible, these challenges
will take the form

>> of

>> friendly competitions with defined parameters, data, a scoring
system,

>> and "winners", to be established along with other
unpublished results

>> only at the meeting, as is tradition at GRCs.

>>

>> But what are the principle challenges in biological structure

>> determination today?  I of course have my own ideas,
but I feel like

>> I'm

>> forgetting something.  Obvious choices are:

>> 1) getting crystals to diffract better

>> 2) building models into low-resolution maps (after failing at
#1)

>> 3) telling if a ligand is really there or not

>> 4) the phase problem (dealing with weak signal, twinning and

>> pseudotranslation)

>> 5) what does "resolution" really mean?

>> 6) why are macromolecular R factors so much higher than
small-molecule

>> ones?

>> 7) what is the best way to process serial crystallography
data?

>> 8) how should one deal with non-isomorphism in multi-crystal
methods?

>> 9) what is the "structure" of something that won't sit
still?

>>

>> What am I missing?  Is industry facing different
problems than

>> academics?  Are there specific challenges facing
electron-based

>> techniques?  If so, could the combined strength of
all the world's

>> methods developers solve them?  I'm interested in
hearing the voice of

>> this community.  On or off-list is fine.

>>

>> -James Holton

>> MAD Scientist

>>

>>

>>


>>

>> To unsubscribe from the CCP4BB list, click the following link:

>>
https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1

>

> --

> --

> Tim Gruene

> Head of the Centre for X-ray Structure Analysis

> Faculty of Chemistry

> University of Vienna

>

> Phone: +43-1-4277-70202

>

> GPG Key ID = A46BEE1A

>

>


>

> To unsubscribe from the CCP4BB list, click the following link:

> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1

>



To unsubscribe from the CCP4BB list, click the following link:
https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1

Re: [ccp4bb] challenges in structural biology

[Minmin Yu]

Hi James, 
7) or 8) What are a few different collection methods
including at RT for serial crystallography data?
Temperature vs global and site-specific radiation damage  ---
RT serial crystallography
            Temperature vs multiple
conformers 
 
Thanks,
Minmin
 
> Dear James,

>

> 10) are the biological questions that you can answer with a
(crystal)

> structure sufficiently relevant to justify the resources?

>

> Best,

> Tim

>

>

>

> Am 15.07.2019 21:44, schrieb Holton, James M:

>> Hello folks,

>>

>> I have the distinct honor of chairing the next Gordon Research

>> Conference on Diffraction Methods in Structural Biology (July
26-31

>> 2020).  This meeting will focus on the biggest
challenges currently

>> faced by structural biologists, and I mean actual real-world

>> challenges.  As much as possible, these challenges
will take the form

>> of

>> friendly competitions with defined parameters, data, a scoring
system,

>> and "winners", to be established along with other
unpublished results

>> only at the meeting, as is tradition at GRCs.

>>

>> But what are the principle challenges in biological structure

>> determination today?  I of course have my own ideas,
but I feel like

>> I'm

>> forgetting something.  Obvious choices are:

>> 1) getting crystals to diffract better

>> 2) building models into low-resolution maps (after failing at
#1)

>> 3) telling if a ligand is really there or not

>> 4) the phase problem (dealing with weak signal, twinning and

>> pseudotranslation)

>> 5) what does "resolution" really mean?

>> 6) why are macromolecular R factors so much higher than
small-molecule

>> ones?

>> 7) what is the best way to process serial crystallography
data?

>> 8) how should one deal with non-isomorphism in multi-crystal
methods?

>> 9) what is the "structure" of something that won't sit
still?

>>

>> What am I missing?  Is industry facing different
problems than

>> academics?  Are there specific challenges facing
electron-based

>> techniques?  If so, could the combined strength of
all the world's

>> methods developers solve them?  I'm interested in
hearing the voice of

>> this community.  On or off-list is fine.

>>

>> -James Holton

>> MAD Scientist

>>

>>

>>


>>

>> To unsubscribe from the CCP4BB list, click the following link:

>>
https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1

>

> --

> --

> Tim Gruene

> Head of the Centre for X-ray Structure Analysis

> Faculty of Chemistry

> University of Vienna

>

> Phone: +43-1-4277-70202

>

> GPG Key ID = A46BEE1A

>

>


>

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Re: [ccp4bb] challenges in structural biology

[Minmin Yu]

Hi James, 
7) or 8) What are a few different collection methods
including at RT for serial crystallography data?
Temperature vs global and site-specific radiation damage  ---
RT serial crystallography
            Temperature vs multiple
conformers 
 
Thanks,
Minmin
 
> Dear James,

>

> 10) are the biological questions that you can answer with a
(crystal)

> structure sufficiently relevant to justify the resources?

>

> Best,

> Tim

>

>

>

> Am 15.07.2019 21:44, schrieb Holton, James M:

>> Hello folks,

>>

>> I have the distinct honor of chairing the next Gordon Research

>> Conference on Diffraction Methods in Structural Biology (July
26-31

>> 2020).  This meeting will focus on the biggest
challenges currently

>> faced by structural biologists, and I mean actual real-world

>> challenges.  As much as possible, these challenges
will take the form

>> of

>> friendly competitions with defined parameters, data, a scoring
system,

>> and "winners", to be established along with other
unpublished results

>> only at the meeting, as is tradition at GRCs.

>>

>> But what are the principle challenges in biological structure

>> determination today?  I of course have my own ideas,
but I feel like

>> I'm

>> forgetting something.  Obvious choices are:

>> 1) getting crystals to diffract better

>> 2) building models into low-resolution maps (after failing at
#1)

>> 3) telling if a ligand is really there or not

>> 4) the phase problem (dealing with weak signal, twinning and

>> pseudotranslation)

>> 5) what does "resolution" really mean?

>> 6) why are macromolecular R factors so much higher than
small-molecule

>> ones?

>> 7) what is the best way to process serial crystallography
data?

>> 8) how should one deal with non-isomorphism in multi-crystal
methods?

>> 9) what is the "structure" of something that won't sit
still?

>>

>> What am I missing?  Is industry facing different
problems than

>> academics?  Are there specific challenges facing
electron-based

>> techniques?  If so, could the combined strength of
all the world's

>> methods developers solve them?  I'm interested in
hearing the voice of

>> this community.  On or off-list is fine.

>>

>> -James Holton

>> MAD Scientist

>>

>>

>>


>>

>> To unsubscribe from the CCP4BB list, click the following link:

>>
https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1

>

> --

> --

> Tim Gruene

> Head of the Centre for X-ray Structure Analysis

> Faculty of Chemistry

> University of Vienna

>

> Phone: +43-1-4277-70202

>

> GPG Key ID = A46BEE1A

>

>


>

> To unsubscribe from the CCP4BB list, click the following link:

> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1

>



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Re: [ccp4bb] challenges in structural biology

[Minmin Yu]

Hi James, 
7) or 8) What are a few different collection methods
including at RT for serial crystallography data?
Temperature vs global and site-specific radiation damage  ---
RT serial crystallography
            Temperature vs multiple
conformers 
 
Thanks,
Minmin
 
> Dear James,

>

> 10) are the biological questions that you can answer with a
(crystal)

> structure sufficiently relevant to justify the resources?

>

> Best,

> Tim

>

>

>

> Am 15.07.2019 21:44, schrieb Holton, James M:

>> Hello folks,

>>

>> I have the distinct honor of chairing the next Gordon Research

>> Conference on Diffraction Methods in Structural Biology (July
26-31

>> 2020).  This meeting will focus on the biggest
challenges currently

>> faced by structural biologists, and I mean actual real-world

>> challenges.  As much as possible, these challenges
will take the form

>> of

>> friendly competitions with defined parameters, data, a scoring
system,

>> and "winners", to be established along with other
unpublished results

>> only at the meeting, as is tradition at GRCs.

>>

>> But what are the principle challenges in biological structure

>> determination today?  I of course have my own ideas,
but I feel like

>> I'm

>> forgetting something.  Obvious choices are:

>> 1) getting crystals to diffract better

>> 2) building models into low-resolution maps (after failing at
#1)

>> 3) telling if a ligand is really there or not

>> 4) the phase problem (dealing with weak signal, twinning and

>> pseudotranslation)

>> 5) what does "resolution" really mean?

>> 6) why are macromolecular R factors so much higher than
small-molecule

>> ones?

>> 7) what is the best way to process serial crystallography
data?

>> 8) how should one deal with non-isomorphism in multi-crystal
methods?

>> 9) what is the "structure" of something that won't sit
still?

>>

>> What am I missing?  Is industry facing different
problems than

>> academics?  Are there specific challenges facing
electron-based

>> techniques?  If so, could the combined strength of
all the world's

>> methods developers solve them?  I'm interested in
hearing the voice of

>> this community.  On or off-list is fine.

>>

>> -James Holton

>> MAD Scientist

>>

>>

>>


>>

>> To unsubscribe from the CCP4BB list, click the following link:

>>
https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1

>

> --

> --

> Tim Gruene

> Head of the Centre for X-ray Structure Analysis

> Faculty of Chemistry

> University of Vienna

>

> Phone: +43-1-4277-70202

>

> GPG Key ID = A46BEE1A

>

>


>

> To unsubscribe from the CCP4BB list, click the following link:

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>



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Re: [ccp4bb] challenges in structural biology

[Nukri Sanishvili]

I know it is going to hijack the original topic but I could not help...

“The reports of death of (macromolecular) crystallography are greatly
exaggerated.
If we believed the prognosticators, it has been dead since the 80s when
some folks made the claim that the only relevant structures were those
solved by NMR.
I think we've done quite well since then...
Best,
Nukri

On Mon, Jul 15, 2019 at 3:45 PM  wrote:

> Hi Tassos, Tim,
>
> I wonder why would you or anyone on this list worry whether biological
> questions that can be asked and answered with structures are relevant to
> justify the resources? I think there is abundant evidence that this is the
> case. Unless your point is that crystallography is now dead for all
> practical
> purposes... then yes, I fully agree :-) It would however be wrong to erase
> its
> historical contribution to understanding biology.
>
> Best wishes,
>
> Radu
>
>
> > I would wonder more if the biological questions you can *ask* with a
> (crystal)
> > structure are sufficiently relevant to justify the resources.
> >
> > Sent from my iPhone
> >
> >> On 15 Jul 2019, at 22:08, Tim Grüne  wrote:
> >>
> >> Dear James,
> >>
> >> 10) are the biological questions that you can answer with a (crystal)
> >> structure sufficiently relevant to justify the resources?
> >>
> >> Best,
> >> Tim
> >>
> >>
> >>
> >> Am 15.07.2019 21:44, schrieb Holton, James M:
> >>> Hello folks,
> >>> I have the distinct honor of chairing the next Gordon Research
> >>> Conference on Diffraction Methods in Structural Biology (July 26-31
> >>> 2020).  This meeting will focus on the biggest challenges currently
> >>> faced by structural biologists, and I mean actual real-world
> >>> challenges.  As much as possible, these challenges will take the form
> of
> >>> friendly competitions with defined parameters, data, a scoring system,
> >>> and "winners", to be established along with other unpublished results
> >>> only at the meeting, as is tradition at GRCs.
> >>> But what are the principle challenges in biological structure
> >>> determination today?  I of course have my own ideas, but I feel like
> I'm
> >>> forgetting something.  Obvious choices are:
> >>> 1) getting crystals to diffract better
> >>> 2) building models into low-resolution maps (after failing at #1)
> >>> 3) telling if a ligand is really there or not
> >>> 4) the phase problem (dealing with weak signal, twinning and
> >>> pseudotranslation)
> >>> 5) what does "resolution" really mean?
> >>> 6) why are macromolecular R factors so much higher than small-molecule
> >>> ones?
> >>> 7) what is the best way to process serial crystallography data?
> >>> 8) how should one deal with non-isomorphism in multi-crystal methods?
> >>> 9) what is the "structure" of something that won't sit still?
> >>> What am I missing?  Is industry facing different problems than
> >>> academics?  Are there specific challenges facing electron-based
> >>> techniques?  If so, could the combined strength of all the world's
> >>> methods developers solve them?  I'm interested in hearing the voice of
> >>> this community.  On or off-list is fine.
> >>> -James Holton
> >>> MAD Scientist
> >>>
> 
> >>> To unsubscribe from the CCP4BB list, click the following link:
> >>> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1
> >>
> >> --
> >> --
> >> Tim Gruene
> >> Head of the Centre for X-ray Structure Analysis
> >> Faculty of Chemistry
> >> University of Vienna
> >>
> >> Phone: +43-1-4277-70202
> >>
> >> GPG Key ID = A46BEE1A
> >>
> >> 
> >>
> >> To unsubscribe from the CCP4BB list, click the following link:
> >> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1
> >
> > 
> >
> > To unsubscribe from the CCP4BB list, click the following link:
> > https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1
> >
>
>
> --
> Radu Aricescu
> MRC Laboratory of Molecular Biology
> Francis Crick Avenue
> Cambridge Biomedical Campus
> Cambridge CB2 0QH, U.K.
> tel: +44-(0)1223-267049
> fax: +44-(0)1223-268305
> www: http://www2.mrc-lmb.cam.ac.uk/group-leaders/a-to-g/radu-aricescu
>
> 
>
> To unsubscribe from the CCP4BB list, click the following link:
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>



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Re: [ccp4bb] challenges in structural biology

[Anastassis Perrakis]

I would wonder more if the biological questions you can *ask* with a (crystal) 
structure are sufficiently relevant to justify the resources. 

Sent from my iPhone

> On 15 Jul 2019, at 22:08, Tim Grüne  wrote:
> 
> Dear James,
> 
> 10) are the biological questions that you can answer with a (crystal) 
> structure sufficiently relevant to justify the resources?
> 
> Best,
> Tim
> 
> 
> 
> Am 15.07.2019 21:44, schrieb Holton, James M:
>> Hello folks,
>> I have the distinct honor of chairing the next Gordon Research
>> Conference on Diffraction Methods in Structural Biology (July 26-31
>> 2020).  This meeting will focus on the biggest challenges currently
>> faced by structural biologists, and I mean actual real-world
>> challenges.  As much as possible, these challenges will take the form of
>> friendly competitions with defined parameters, data, a scoring system,
>> and "winners", to be established along with other unpublished results
>> only at the meeting, as is tradition at GRCs.
>> But what are the principle challenges in biological structure
>> determination today?  I of course have my own ideas, but I feel like I'm
>> forgetting something.  Obvious choices are:
>> 1) getting crystals to diffract better
>> 2) building models into low-resolution maps (after failing at #1)
>> 3) telling if a ligand is really there or not
>> 4) the phase problem (dealing with weak signal, twinning and
>> pseudotranslation)
>> 5) what does "resolution" really mean?
>> 6) why are macromolecular R factors so much higher than small-molecule ones?
>> 7) what is the best way to process serial crystallography data?
>> 8) how should one deal with non-isomorphism in multi-crystal methods?
>> 9) what is the "structure" of something that won't sit still?
>> What am I missing?  Is industry facing different problems than
>> academics?  Are there specific challenges facing electron-based
>> techniques?  If so, could the combined strength of all the world's
>> methods developers solve them?  I'm interested in hearing the voice of
>> this community.  On or off-list is fine.
>> -James Holton
>> MAD Scientist
>> 
>> To unsubscribe from the CCP4BB list, click the following link:
>> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1
> 
> -- 
> --
> Tim Gruene
> Head of the Centre for X-ray Structure Analysis
> Faculty of Chemistry
> University of Vienna
> 
> Phone: +43-1-4277-70202
> 
> GPG Key ID = A46BEE1A
> 
> 
> 
> To unsubscribe from the CCP4BB list, click the following link:
> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1



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[ccp4bb] challenges in structural biology

[Holton, James M]

Hello folks,

I have the distinct honor of chairing the next Gordon Research 
Conference on Diffraction Methods in Structural Biology (July 26-31 
2020).  This meeting will focus on the biggest challenges currently 
faced by structural biologists, and I mean actual real-world 
challenges.  As much as possible, these challenges will take the form of 
friendly competitions with defined parameters, data, a scoring system, 
and "winners", to be established along with other unpublished results 
only at the meeting, as is tradition at GRCs.

But what are the principle challenges in biological structure 
determination today?  I of course have my own ideas, but I feel like I'm 
forgetting something.  Obvious choices are:
1) getting crystals to diffract better
2) building models into low-resolution maps (after failing at #1)
3) telling if a ligand is really there or not
4) the phase problem (dealing with weak signal, twinning and 
pseudotranslation)
5) what does "resolution" really mean?
6) why are macromolecular R factors so much higher than small-molecule ones?
7) what is the best way to process serial crystallography data?
8) how should one deal with non-isomorphism in multi-crystal methods?
9) what is the "structure" of something that won't sit still?

What am I missing?  Is industry facing different problems than 
academics?  Are there specific challenges facing electron-based 
techniques?  If so, could the combined strength of all the world's 
methods developers solve them?  I'm interested in hearing the voice of 
this community.  On or off-list is fine.

-James Holton
MAD Scientist




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