Re: [ccp4bb] Crystal optimization

[Frank Von Delft]

Usually, you should try to push up the protein concentration, often quite a lot 
(30, 50, even 100 mg/ml), and decrease precipitant (might have to be really 
low, eg <3% PEG is not unthinkable).

To get the protein up, you may need to find a new buffer solution - there are 
screens for this, and DSF is one way to test. But might need a new construct or 
surface mutation or other protein engineering.

Good luck
Frank

Sent from tiny silly touch screen


From: 白雪慧 
Sent: Friday, 31 May 2024 03:33
To: CCP4BB@JISCMAIL.AC.UK
Subject: [ccp4bb] Crystal optimization

Thank you very much for your suggestions. I have a question. My crystal grows 
microcrystals under multiple conditions, as shown in the figure. After 
orthogonal optimization of the precipitant and pH, the crystal growth is still 
very small and difficult to obtain diffraction. What is the method to optimize 
and increase the crystal size in this situation?




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Re: [ccp4bb] AlphaFold3 Transparency and Reproducibility

[Frank von Delft]

What we really need is a tweet from Nature, declaring their 
embarrassment at having been suckered into becoming DeepMind's 
advertising arm.



On 14/05/2024 01:56, Paul Adams wrote:


The letter may have had (or helped have) an impact already:

On X today from Pushmeet Kohli @ DeepMind

"We love the excitement & results from the community on AlphaFold 3 
and are doubling the AF Server daily job limit to 20. Happy to also 
share that we're working on releasing the AF3 model (incl weights) for 
academic use, which doesn’t depend on our research infra, within 6 
months".



On May 13, 2024, at 11:11 AM, Wankowicz, Stephanie 
 wrote:


If it does what it claims – incredibly impressive. The issue we have 
is there is no way to verify or validate the claims it is making.


The letter is a call and start of a conversation about how the 
ever-changing landscape of communication and publication of science 
should be.


-Stephanie Wankowicz

*From:*CCP4 bulletin board  on behalf of 
Krieger, James M 

*Sent:*Monday, May 13, 2024 10:22 AM
*To:*CCP4BB@JISCMAIL.AC.UK
*Subject:*Re: [ccp4bb] Fwd: AlphaFold3 Transparency and Reproducibility
This Message Is From an External Sender
This message came from outside your organization.
It definitely is impressive but it also has clear limitations

On 13 May 2024, at 15:22, Sylvia Fanucchi 
 wrote:





You don't often get email from 
d0c4e77ae410-dmarc-requ...@jiscmail.ac.uk.Learn why this is 
important 




Is it just me who is really impressed by it? Am I missing something?

GetOutlook for Android 



*From:*CCP4 bulletin board  on behalf of 
Rafael Marques 

*Sent:*Monday, May 13, 2024 3:13:16 PM
*To:*CCP4BB@JISCMAIL.AC.UK 
*Subject:*Re: [ccp4bb] Fwd: AlphaFold3 Transparency and Reproducibility
I tried it yesterday and I was really shocked by how fast it is. 
When I was preparing to submit my second job, the first one was 
already finished, which made me think that I was definitely doing 
something wrong. Probably I was...


Best wishes

Rafael Marques


On 13 May 2024 09:53, Harry Powell 
<193323b1e616-dmarc-requ...@jiscmail.ac.uk> wrote:


Hi folks

This arrived in my inbox this morning, and I believe that it may
provoke some discussion…

Wikipedia tells me: στέργει γὰρ οὐδεὶς ἄγγελον κακῶν ἐπῶν

Best wishes!

Harry

>    From: Stephanie Wankowicz 
>    Sent: Saturday, May 11, 2024 3:31 PM
>    To: James Fraser ; Pedro Beltrao
; Benjamin Cravatt
; Roland Dunbrack
; Anthony Gitter
; Kresten Lindorff-Larsen
; Sergey Ovchinnikov ; Polizzi,
Nicholas F. ; Brian Shoichet

>    Subject: AlphaFold3 Transparency and Reproducibility
>
>
>    This email from mullane.stepha...@gmail.com originates from
outside Imperial. Do not click on links and attachments unless
you recognise the sender. If you trust the sender, add them to
your safe senders list


to
disable email stamping for this address.
>
>    Hello,
>
>
>    As many of you, we were incredibly disappointed with the
lack of code or even executables accompanying the publication of
AlphaFold3 in Nature. AlphaFold3 was released without the means
to test and use the software in a high-throughput manner. This
does not align with the principles of scientific research, which
rely on the ability of the community to evaluate, use, and build
upon existing work.
>
>
>
>    We have written a letter, which will be posted on Zenodo
and submitted as a Letter to the Editor in the coming days.
>
>
>
>    Please see the entire letter here.



If
you want to endorse this letter, please fill out your name,
affiliation, and email in the form.
>
>
>
>    

Re: [ccp4bb] Rescale merged data?

[Frank von Delft]

Is it easy/non-arcane or indeed automatic for non-experts to add these 
loops?  Because that's the only way this will be achieved systemically.


Presumably ccp4i2 can be wrangled into making it happen magically. 
(Apologies if it does already, if so, a comment here would help the 
discussion...)


Frank



On 18/04/2024 11:02, Randy John Read wrote:

I’d like to add my strong agreement to what Robbie said, but also point out a 
wrinkle. When the PDB runs validation, it just takes the data that are in the 
first reflection loop of the reflections.cif file. So if you want the 
validation statistics to match your reported refinement statistics, that loop 
should contain the set of data you gave the refinement program, especially if 
you’ve done something like apply an elliptical truncation, correct for 
anisotropy, or convert intensities to amplitudes, all of which change the data 
in ways that can’t be reversed later. Whenever you’ve done any of this (and 
many people are using StarAniso these days, which does all of those things), 
please put in a second reflection loop containing the whole set of intensities 
to the highest resolution you used, without any anisotropic scaling or 
elliptical cutoffs. Then anyone wanting to re-refine your structure or check 
your data for artefacts will have more information available.

Of course, I hope we’re moving to a world in which we all also deposit the 
intensities before merging, which in principle allows even more quality control 
to be done.

Best wishes,

Randy Read


On 18 Apr 2024, at 05:04, Robbie Joosten  wrote:

If I may add to that: Please deposit the full dataset, not just the set of 
reflections you end up using. This allows people to use all the data if they 
are interested.

Cheers,
Robbie

On 17 Apr 2024 22:35, "Hekstra, Doeke Romke"  wrote:
Hi Matt,
  
I appreciate disagreement and comments from colleagues. My two cents are that it seems unnecessary to repeat scaling and merging, or any earlier step. If you want to remove structure factor amplitudes or merged intensities from the MTZ file you can do so using MTZUTILS or similar functionality in CCP4 (https://www.ccp4.ac.uk/html/mtzutils.html#generalresolution). For refinement, you can specify the desired resolution range in your favorite refinement program.
  
My personal convention is to use CC1/2 = 0.30 as the point to which retain data and  = 2 as the nominal resolution of the dataset. If you have the HKL2000 scaling log, you should be able to retrieve this information. I frankly wish we’d just deposit all data in the PDB rather than truncate based on some criterion or another.
  
Best, Doeke
  
From: Matt Mcleod 

Sent: Wednesday, April 17, 2024 4:12 PM
To: Hekstra, Doeke Romke 
Cc: CCP4BB@JISCMAIL.AC.UK
Subject: Re: [ccp4bb] Rescale merged data?
  
Sure thing.
  
A former student left somewhere between 30-50 datasets but they scaled the data to the detector corners (or maybe edge) in HKL2000.  There are many of the high-resolution bins with no reflections in them.  He then went forward and merged this data, presumably in HKL2000 again and did his model building/refinement.   We now need to re-refine the models against this data for publication but we need a more suitable resolution cutoff for the data.
  
Rather than go back and index/integrate all the data and then rescale the data to a more appropriate place (then merge), I was wondering if there was a way to take the merged reflections as either .sca or .mtz (from scalepacktomtz output) and then rescale to a more appropriate resolution.  It doesn't seem like the student left unmerged data.
  
So, nothing fancy (aniostropy etc), there is just a lot of data that needs to be adjusted and I am trying to avoid reprocessing all the frames again.
  
Matt
  
On Wed, 17 Apr 2024 at 15:59, Hekstra, Doeke Romke  wrote:

Hi Matt,

It would be helpful if you could describe your case in more detail. Do you want 
to change the resolution cutoff after scaling? Do you want to keep more data? 
Fewer? Or do you mean something different such as truncation to generate 
amplitudes, application of anisotropic resolution cutoffs,  or outlier 
rejection? Are you referring to data that were scaled in HKL2000?

Best, Doeke

-Original Message-
From: CCP4 bulletin board  On Behalf Of Matt McLeod
Sent: Wednesday, April 17, 2024 3:04 PM
To: CCP4BB@JISCMAIL.AC.UK
Subject: [ccp4bb] Rescale merged data?

Hi all,

I am looking at a old students data and it looks like they didn't properly cut 
off the data during scaling.  All of the files I have appear to be the merged 
.sca (or mtz after converting with scalepacktomtz) - is there a way to 
retruncate the data after merging or do I have to reprocess the data?

Thanks,



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Re: [ccp4bb] request for applications

[Frank Von Delft]

Oh dear, your prime number oversupply crashed the crypto Ponzi scheme market.  
Will you accept $10e2 proposals now?

Sent from tiny silly touch screen

From: James Holton 
Sent: Monday, 1 April 2024 08:01
To: CCP4BB@JISCMAIL.AC.UK
Subject: [ccp4bb] request for applications

Hey Everyone,

It may sound like an incredibly boring thing that there has never been a
formal mathematical proof that finding the prime factors of very large
numbers doesn't have a more efficient algorithm than simply trying every
single one of them. Nevertheless, to this day, encryption keys and
indeed blockchain-based cryptocurrencies hinge upon how computationally
hard it is to find these large prime factors. And yet, no one has ever
proven that there is not a more efficient way.

It occurred to me recently that cryptocurrencies (blockchains) are
nothing more than a sequence of numbers, and Large Language Models
fundamentally take a sequence of "words" and predict the next one in the
series. So, they seem naturally suited to the task of finding a more
efficient way. I spent some of my free time trying my hand at this.
There were some twists and turns along the way, but as of today it seems
to be working. Predictions are now coming pretty fast. By the end of
April 1, I expect to have ~ $1e12 USD on current ledgers. This may have
certain socioeconomic ramifications, but that is not what I want to
discuss here. What I want to discuss is how to use this new source of
scientific funding!

My question for the BB is: what would YOU do if you had $1e12 USD for
your science? No non-scientific proposals please. There are plenty of
other forums for those.  This BB is about biological structural science,
so please stay on-topic.  OK?  And now: suggestions!

I am particularly interested in projects that can only be done with a
large, cooperative $1e12 USD, but not by 10e6 independent and unrelated
$100e3 projects. The Apollo moon missions, for example cost $300e9
(adjusted USD).  On a smaller scale, re-doing the whole PDB from cloning
and expression to crystallization and structure solution would only cost
about $500e6 USD. That would finally give us a good database of
crystallization conditions for training an AI to tell you, given a
sequence, what the crystallization conditions (if any) will be. That
might take a lot of computing power, but there is plenty left over to
buy 10 zettaflops of computing power (and the solar panels needed to
power it). Or, if we really want to just divide it up, that would be
$10e6 for each of the ~1e5 people on this planet who fit into the
category of "biological scientist". That's not just PIs, but postdocs,
grad students, techs. Everybody.

I'm sure this will solve a lot of problems, but not all of them. And, I
like to get ahead of things. So, what are the non-financial problems
that will remain?  I think these are the most important problems in
science: the intellectual and technological hurdles that money can't
overcome.  I'm hoping this will be an opportunity for all of us to focus
on those.  I know we're all not used to thinking on this scale, but, at
least for today, let's give it a try!

Looking forward to your applications,

-James Holton
MAD Scientist



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From: James Holton 
Sent: Monday, 1 April 2024 08:01
To: CCP4BB@JISCMAIL.AC.UK
Subject: [ccp4bb] request for applications

Hey Everyone,

It may sound like an incredibly boring thing that there has never been a
formal mathematical proof that finding the prime factors of very large
numbers doesn't have a more efficient algorithm than simply trying every
single one of them. Nevertheless, to this day, encryption keys and
indeed blockchain-based cryptocurrencies hinge upon how computationally
hard it is to find these large prime factors. And yet, no one has ever
proven that there is not a more efficient way.

It occurred to me recently that cryptocurrencies (blockchains) are
nothing more than a sequence of numbers, and Large Language Models
fundamentally take a sequence of "words" and predict the next one in the
series. So, they seem naturally suited to the task of finding a more
efficient way. I spent some of my free time trying my hand at this.
There were some twists and turns along the way, but as of today it seems
to be working. Predictions are now coming pretty fast. By the end of
April 1, I expect to have ~ $1e12 USD on current ledgers. This may have
certain socioeconomic ramifications, but that is not what I want to
discuss here. What I want to discuss is how to use this new source of
scientific 

Re: [ccp4bb] Crystallizing a tough target

[Frank von Delft]

Don't forget to try pure water.

On 05/02/2024 10:44, Savvas Savvides wrote:

Dear Kavya,

we encountered this issue for a protein complex at 95 mg/mL involving 
Human Serum Albumin (HSA) and a designed protein binder (Alphabody) as 
described in Pannecoucke et al. 2021 Sci Adv 7 (13), 
DOI:10.1126/sciadv.abe1682.
The breakthrough in that case came from crystallization experiments at 
different temperatures (14C, 21C and 37C), with 37C coming out as the 
clear winner.


best wishes
Savvas


——
Prof. Savvas Savvides
VIB Center for Inflammation Research
Ghent University, Dept. of Biochemistry & Microbiology
Technologiepark 71, 9052 Ghent, Belgium

Email: savvas.savvi...@ugent.be ; savvas.savvi...@irc.vib-ugent.be
Phone: +32 (0)472 928 519 (mobile) ; +32 (0)9 331 36 60 (office)
Web:_https://www.irc.ugent.be/index.php/groups/savvides-unit_


On 5 Feb 2024, at 11:27, kavyashreem  wrote:

Dear All,

Has anyone worked on a protein which is highly soluble even at 80mg/ml?

We have one such candidate, which does not precipitate even at 
80mg/ml instead forms phase separated globules in crystallization 
plate, which eventually hardens over a period of 1 to 1.5 months 
(which is florescent under UV microscope.)


We tried screening at different pH, but failed to get any hits.

Since we got few conditions in which the phase separated globules 
solidified, we focused on them and expanded with 120mg/ml protein, 
still there were not visible precipitates except for the phase 
separation. This has been a challenging target so far. We have tried 
with different constructs, which unfortunately are not soluble!


Does POMs help in such cases? Or do you have any other suggestion.

Thank you

Regards

Kavya





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Re: [ccp4bb] PDBe Unveils New Streamlined FTP Structure and Enhanced Ligand Data Files

[Frank von Delft]

That's great news!

On 01/02/2024 10:34, Deborah Harrus wrote:


Dear Frank,

We are indeed harvesting restraints used in refinement, but not 
distributing them yet. This should come later this year or early 2025, 
and can be made retrospectively.


Kind regards,

Deborah

On 31/01/2024 14:15, Frank von Delft wrote:

Hi Deborah - sounds great, well done!

Are you yet harvesting and serving up the restraints used in 
refinement?  If not, that remains a huge gap, in my view.  (The 
chemists tend not to be aware that's even a thing, I keep discovering.)


Frank


On 31/01/2024 13:57, Deborah Harrus wrote:


*Dear all,*

*We're excited to announce significant improvements to ligand data 
access and organisation within the PDBe FTP area. These updates aim 
to empower your research by simplifying data retrieval and providing 
deeper insights into protein-ligand interactions.*


*Key Enhancements:*

 *

*Comprehensive Ligand Interaction Data: Two new data files,
Interacting_chains_with_ligand_functions.tsv and
pdb_bound_molecules.tsv, enable large-scale analyses of ligand
interactions across the entire PDB archive including functional
categorisation such as drug-like, reactant-like or cofactor-like.*

 *

*Streamlined FTP Directory Structure: The revamped FTP area
features dedicated folders for Chemical Component Definitions
(CCDs), Peptide-like Reference Definitions (PRDs), Covalently
Linked Components (CLCs), and additional data files,
facilitating intuitive data navigation.*

*Benefits for You:*

 *

*Perform large-scale ligand interaction analyses across the
entire PDB using complete ligand representations.*

 *

*Quick access to all the ligands bound to a specific protein or
identifying all the proteins binding to a specific ligand*

 *

*Gain deeper insights into protein function through ligand
interaction and classification.*

 *

*Easily access and navigate ligand data with clear file
organisation and unique identifiers.*

*We believe these improvements will enhance ligand data analysis 
through streamlined data access and additional functional insights. *


*For more information, visit the PDBe news item 
at:https://www.ebi.ac.uk/pdbe/news/improved-access-ligand-data-and-annotations-pdbe-ftp 
<https://www.ebi.ac.uk/pdbe/news/improved-access-ligand-data-and-annotations-pdbe-ftp>*


*Or visit the PDBe FTP area 
directly:https://ftp.ebi.ac.uk/pub/databases/msd/pdbechem_v2/ 
<https://ftp.ebi.ac.uk/pub/databases/msd/pdbechem_v2/>*


*Should you have any questions or require further assistance, please 
don't hesitate to contact us.*


*

Sincerely,

Deborah Harrus

The PDBe Team

*
--
---
Deborah Harrus, Ph.D.
PDBe Archive Project Leader, Biocuration Lead
PDBe - Protein Data Bank in Europe

European Bioinformatics Institute (EMBL-EBI)
European Molecular Biology Laboratory
Wellcome Trust Genome Campus
Hinxton
Cambridge CB10 1SD UK

http://www.PDBe.org
---



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--
---
Deborah Harrus, Ph.D.
PDBe Archive Project Leader, Biocuration Lead
PDBe - Protein Data Bank in Europe

European Bioinformatics Institute (EMBL-EBI)
European Molecular Biology Laboratory
Wellcome Trust Genome Campus
Hinxton
Cambridge CB10 1SD UK

http://www.PDBe.org
---





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Re: [ccp4bb] PDBe Unveils New Streamlined FTP Structure and Enhanced Ligand Data Files

[Frank von Delft]

Hi Deborah - sounds great, well done!

Are you yet harvesting and serving up the restraints used in 
refinement?  If not, that remains a huge gap, in my view.  (The chemists 
tend not to be aware that's even a thing, I keep discovering.)


Frank


On 31/01/2024 13:57, Deborah Harrus wrote:


*Dear all,*

*We're excited to announce significant improvements to ligand data 
access and organisation within the PDBe FTP area. These updates aim to 
empower your research by simplifying data retrieval and providing 
deeper insights into protein-ligand interactions.*


*Key Enhancements:*

 *

*Comprehensive Ligand Interaction Data: Two new data files,
Interacting_chains_with_ligand_functions.tsv and
pdb_bound_molecules.tsv, enable large-scale analyses of ligand
interactions across the entire PDB archive including functional
categorisation such as drug-like, reactant-like or cofactor-like.*

 *

*Streamlined FTP Directory Structure: The revamped FTP area
features dedicated folders for Chemical Component Definitions
(CCDs), Peptide-like Reference Definitions (PRDs), Covalently
Linked Components (CLCs), and additional data files, facilitating
intuitive data navigation.*

*Benefits for You:*

 *

*Perform large-scale ligand interaction analyses across the entire
PDB using complete ligand representations.*

 *

*Quick access to all the ligands bound to a specific protein or
identifying all the proteins binding to a specific ligand*

 *

*Gain deeper insights into protein function through ligand
interaction and classification.*

 *

*Easily access and navigate ligand data with clear file
organisation and unique identifiers.*

*We believe these improvements will enhance ligand data analysis 
through streamlined data access and additional functional insights. *


*For more information, visit the PDBe news item 
at:https://www.ebi.ac.uk/pdbe/news/improved-access-ligand-data-and-annotations-pdbe-ftp 
*


*Or visit the PDBe FTP area 
directly:https://ftp.ebi.ac.uk/pub/databases/msd/pdbechem_v2/ 
*


*Should you have any questions or require further assistance, please 
don't hesitate to contact us.*


*

Sincerely,

Deborah Harrus

The PDBe Team

*
--
---
Deborah Harrus, Ph.D.
PDBe Archive Project Leader, Biocuration Lead
PDBe - Protein Data Bank in Europe

European Bioinformatics Institute (EMBL-EBI)
European Molecular Biology Laboratory
Wellcome Trust Genome Campus
Hinxton
Cambridge CB10 1SD UK

http://www.PDBe.org
---



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[ccp4bb] Recruiting: Science Coordinator - antiviral discovery (14 Jan)

[Frank von Delft]

Happy New Year, all -

We're recruiting a Science Coordinator (Junior or Senior) to our big 
NIAID-funded ASAP Center <https://asapdiscovery.org> for Antiviral Drug 
Discovery (AViDD 
<https://www.niaid.nih.gov/research/antiviral-drug-discovery-centers-pathogens-pandemic-concern>). 



The vacancy webpage is here 
<https://vacancies.diamond.ac.uk/vacancy/science-coordinator-senior-science-coordinator-547045.html>; 
start date is as soon as possible.



The Science Coordinator role seems to appeal to people that enjoy being 
part of big collaborations, know the science intimately, like organising 
and writing, but don't want to follow the postdoc ("bench-scientist") 
route.  If that resonates, take a look at the job description in the 
link above.


Do email me if you have specific questions, that aren't answered in the 
documentation.



Cheers
Frank


Prof Frank von Delft
Professor for Structural Chemical Biology
Principal Beamline Scientist: I04-1/XChem
Diamond Light Source
+44 1235 778997 (office: M,T,T)

Principal Investigator: Protein Crystallography
Centre for Medicines Discovery
Oxford University
Biochemistry Building, South Parks Road, OX1 3QU
+44 1865 617583 (office: W,F)
+44 7471 026103 (mobile)




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Re: [ccp4bb] [pe...@leadszone.live: CCP4 Study Weekend-2024] (fwd)

[Frank von Delft]

I mean, who'd actually want that list anyway?!

On 15/12/2023 13:23, Gerard Bricogne wrote:

Dear all,

  I just received this a moment ago, and it looks most suspicious. Can
any action be taken, other than warn people not to follow up?

  Best wishes,

 Gerard

- Forwarded message from Pedro Noel  -

Date: Fri, 15 Dec 2023 13:13:19 +
From: Pedro Noel 
Subject: CCP4 Study Weekend-2024
To: "g...@globalphasing.com" 

Hi ,

Would you be interested in acquiring the attendees list of "CCP4 Study Weekend 
2024"



  Each record constitutes details such as: Company Name, URL, Contact Name, 
Title, Verified Email Addresses, Contact Number, Physical Address etc.



Let me know if your interest and I will revert back with pricing and other 
deliverables.


Regards,
Pedro Noel

- End forwarded message -



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Re: [ccp4bb] The experiment is still very much needed (though AlphaFold helps a lot)

[Frank von Delft]

That's a press release, not a tool that can be tested.


On 01/12/2023 12:19, Roberto Steiner wrote:

Great paper indeed!

However quite significant progress seems to have been achieved with 
ligands as well (and not only)…

https://deepmind.google/discover/blog/a-glimpse-of-the-next-generation-of-alphafold/
Has anyone in the community put this to the test?


Best wishes
Roberto


*Roberto A Steiner*
www.steinerlab.org 
https://twitter.com/steiner_lab
roberto.stei...@kcl.ac.uk
Randall Centre for Cell and Molecular Biophysics
Faculty of Life Sciences and Medicine
King's College London
Room 3.10A
New Hunt's House, Guy's Campus
SE1 1UL, London, UK
Phone 0044 20 78488216
Fax    0044 20 78486435

roberto.stei...@unipd.it
Dipartimento di Scienze Biomediche
Università degli Studi di Padova
Viale G. Colombo 3
35131 Padova, Italia
Telefono 0039 049 8276409

/Responses to emails are not expected outside of your normal working 
hours./









On 30 Nov 2023, at 22:35, Tom Terwilliger 
 wrote:




You don't often get email from 
b6116340b489-dmarc-requ...@jiscmail.ac.uk. Learn why this is 
important 



Hi Structural biologist colleagues!

Our article that helps you make the case that the experiment is still 
very much needed is now out:


https://www.nature.com/articles/s41592-023-02087-4

"AlphaFold predictions are valuable hypotheses and accelerate but do 
not replace experimental structure determination."  Nature Methods (2023)


Also, here is a video on the Phenix Tutorials YouTube channel that 
describes this analysis: https://www.youtube.com/watch?v=ugMPYdPo8Bc


(I hope you will be happy to see that you and your structural biology 
colleagues get the credit for making AlphaFold possible at 2:35 in 
the introduction of this video!  Keep up the fantastic 
structural biology work!)


All the best,
Tom T
--
Thomas C Terwilliger
Laboratory Fellow, Los Alamos National Laboratory
Senior Scientist, New Mexico Consortium
100 Entrada Dr, Los Alamos, NM 87544
Email: tterwilli...@newmexicoconsortium.org
Tel: 505-431-0010




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Re: [ccp4bb] The experiment is still very much needed (though AlphaFold helps a lot)

[Frank von Delft]

Wonderful paper, well done!

On 30/11/2023 21:35, Tom Terwilliger wrote:

Hi Structural biologist colleagues!

Our article that helps you make the case that the experiment is still 
very much needed is now out:


https://www.nature.com/articles/s41592-023-02087-4

"AlphaFold predictions are valuable hypotheses and accelerate but do 
not replace experimental structure determination."  Nature Methods (2023)


Also, here is a video on the Phenix Tutorials YouTube channel that 
describes this analysis: https://www.youtube.com/watch?v=ugMPYdPo8Bc


(I hope you will be happy to see that you and your structural biology 
colleagues get the credit for making AlphaFold possible at 2:35 in the 
introduction of this video!  Keep up the fantastic structural biology 
work!)


All the best,
Tom T
--
Thomas C Terwilliger
Laboratory Fellow, Los Alamos National Laboratory
Senior Scientist, New Mexico Consortium
100 Entrada Dr, Los Alamos, NM 87544
Email: tterwilli...@newmexicoconsortium.org
Tel: 505-431-0010




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[ccp4bb] Posts in advancing fragments: biophysics, informatics

[Frank von Delft]

Hello - I'm recruiting to posts to develop better ways to progress 
fragments to potency.  They're both connected to our antiviral big 
discovery programme 
, and 
part of the XChem team.



_*Biophysics*_:
Can we make sensor-based methods much more useful not, not for fragment 
screening (everyone does that), but to profile large arrays of follow-up 
designs.


   
https://vacancies.diamond.ac.uk/vacancy/postdoctoral-research-associate-antiviral-discovery-biophysics-536706.html
   *Deadline **/this Sunday/* - let me know if you're interested but
   need more time.


_*Computational Chemistry*_**/(postdoc or senior software scientist):/**
Develop infrastructure and algorithms to drive fragment analysis and 
progression.


   
https://vacancies.diamond.ac.uk/vacancy/pdra-or-senior-software-scientist-fragments-computational-chemistry-537294.html
   *Deadline 22nd Oct.*


Let me know if questions.
Frank



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Re: [ccp4bb] in memoriam of Raimond Ravelli

[Frank von Delft]

My word that was a shock to read.  Farewell Raimond, what an amazing 
scientist and person.  Frank



On 05/07/2023 19:54, a.perra...@nki.nl wrote:

Dear all,

It is with profound sadness I announce the passing of Raimond Ravelli, 
one of most remarkable and beloved members of our scientific community.


Raimond first became widely known to the crystallographic community 
with his brilliant “strategy” program in the 90’s, which he developed 
as part of his PhD thesis. Later on, at the EMBL Grenoble and the 
ESRF, Raimond has been instrumental in the development of the ID14-EH4 
beamline, having helped numerous colleagues to collect diffraction 
data and participating in many exciting scientific projects. At that 
time, Raimond also developed his keen interest in radiation damage, 
that influenced the ways that we collect and process X-ray diffraction 
data even today. Raimond came back to his home country, the 
Netherlands, first as an assistant professor at Leiden University, and 
then as associate professor at Maastricht University. During that 
transition he become an expert in cryo-electron microscopy. He made 
numerous contributions also to his new field, in such a broad spectrum 
of techniques, that it would be embarrassing to attempt to enumerate 
them here. I will only mention that one piece of his work even became 
a museum exhibit at the Leiden museum of natural history.


Raimond has been recently appointed Full Professor of Structural 
Biology, at Maastricht University, last November. His inauguration 
speech (Oratie) was simply remarkable. I warmly recommend to anyone to 
watch it at https://youtu.be/Gv3pKRp5S2Y?t=667 . It radiates his 
enthusiasm for science and is inspiring for all, in a way that only he 
himself knew how to do.


Raimond was an accomplished rowing athlete, a formidable cyclist, and 
a hiking enthusiast.


For the many of us who have been his friends it has a been a privilege 
and an inspiration. Raimond, just 55, leaves behind him Maaike, an 
excellent scientist and colleague herself, and their kids Seppe and Noé.


I have no words that could possibly explain how much he will be missed.






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Re: [ccp4bb] how to get mol files from PDB and restraint CIF?

[Frank von Delft]

Really, no CIF needed?

As far as I know, it's only in the CIF file that the precise atom 
identities can be found.  You can infer them from the PDB lines, but 
that rather misses the point.


Frank

On 19/05/2023 10:42, Fred Vellieux wrote:

Hello Frank,

We have to convert betwen file formats very frequently (usually 
several times daily) and:

1) we didn't need any restraints CIF file for that;
2) the tools we are using are
http://www.cheminfo.org/Chemistry/Cheminformatics/FormatConverter/index.html 


https://datascience.unm.edu/tomcat/biocomp/convert

Sometimes the conversion doesn't take place and I have no idea why.

HTH,

Fred.

On 5/19/23 11:28, Frank von Delft wrote:
Hello - as in the subject line, does anybody know of, or have, code 
that will parse (1) a PDB (or mmCIF?) file with a ligand, and (2) the 
restraints CIF file used in refinement, and generate a .mol (or .sdf) 
file?


OpenBabel apparently does not.

I thought the PDB processing tools would, but my collaborator 
couldn't find them.


Any pointers welcome.  (To save us time.)

Thanks!
Frank



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[ccp4bb] how to get mol files from PDB and restraint CIF?

[Frank von Delft]

Hello - as in the subject line, does anybody know of, or have, code that 
will parse (1) a PDB (or mmCIF?) file with a ligand, and (2) the 
restraints CIF file used in refinement, and generate a .mol (or .sdf) file?


OpenBabel apparently does not.

I thought the PDB processing tools would, but my collaborator couldn't 
find them.


Any pointers welcome.  (To save us time.)

Thanks!
Frank



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[ccp4bb] Fwd: Register for the Antiviral Drug Discovery (AViDD) Open Science Forum virtual meeting Wed 15 Feb 11.00A ET

[Frank von Delft]

Hello all - slightly off-topic, but many BB readers will find the talks 
at this forum of direct or indeed indirect interest.


They will run monthly, for as long as the AViDD awards run (currently 
middle 2025), and will cover topics of antiviral drug discovery and 
development, from early discovery all the way to pre-clinical development.


See you there!
Frank


 Forwarded Message 
Subject: 	Register for the Antiviral Drug Discovery (AViDD) Open Science 
Forum virtual meeting Wed 15 Feb 11.00A ET

Date:   Mon, 30 Jan 2023 15:59:46 +
From:   AViDD Open Science Forum 
Reply-To:   AViDD Open Science Forum 
To: frank.von-de...@diamond.ac.uk



Register for the Antiviral Drug Discovery (AViDD) Open Science Forum 
virtual meeting Wed 15 Feb 11.00A ET The next Antiviral Drug Discovery 
(AViDD) Open Science Forum virtual meeting will be Wed 15 Feb 11.00A ET


View this email in your browser 




 Antiviral Drug Discovery (AViDD) Open Science Forum

*ANNOUNCEMENT*

To view slides and recordings from the last *Antiviral Drug Discovery 
(AViDD) Open Science Forum* 
**on 
18 Jan 2023 follow the links below:


 *

   *Presentation slides* can be viewed on**the**Antiviral Drug
   Discovery (AViDD) Open Science Forum Zenodo Community.
   


 *

   *Talk recordings* can be viewed on the AViDD Open Science Forum
   YouTube Channel.
   


The next *Antiviral Drug Discovery (AViDD) Open Science Forum* virtual 
meeting 
 
will be *Wed 15 Feb 2023 at 8.00A PT / 11.00A ET / 4.00P UK (GMT+1) / 
5.00P Geneva (GMT+2)*.


Registration link 



/Moderator:/*John Chodera* 
(MSKCC 
)


 *

   *Brian Shoichet, UCSF*
   
*(**QBI
   Coronavirus Research Group*
   
*)*:
   /False-positives in anti-viral drug discovery: mechanistic bases and
   rapid counterscreening assays /[30 min, recorded]

 *

   *Jesse Bloom, Fred Hutch*
   
*(**ASAP*
   
*)*:
   /Fitness effects of mutations to SARS-CoV-2 proteins /[30 min, recorded]

*Moderated discussion* [30 min, unrecorded]

For a schedule of upcoming events, recorded talks, more information, and 
open antiviral discovery resources, see *http://openantivirals.org* 
.


/The AViDD Open Science Forum is not an official NIAID activity. There 
is no requirement for staff from AViDD Centers or NIH staff to 
participate in this forum./


Register for the virtual AViDD Open Science Forum event 
 




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Re: [ccp4bb] Future Diffraction Methods

[Frank von Delft]

Whether cross-pollination happens depends on the session chairs, and the 
remit they're given, and the instructions given to the speakers:  if 
early on everybody sets the tone, to inform as much as advertise, then 
it could be a rip-roaringly interesting meeting.


At least, I've never encountered a method that was beyond my or any of 
my students' comprehension, at least at some high level, provided we 
were allowed to ask questions about it.


Frank



On 30/01/2023 10:40, Gerard Kleywegt wrote:

Hi all,

I'm a big believer in cross-pollination between disciplines. I think 
there could be room for a multidisciplinary methods meeting (MMM) 
provided the right topics are chosen. If these are things that concern 
NMR-ists, X-ray-ans and cryo-EM-ers equally you might get the right 
mix of people in the room and exchange of ideas and experiences with 
it. For example, all three use Maximum Likelihood (ML) methods. All 
three are or possibly will be interested in applying Machine Learning 
(e, ML) methods (e.g., in cryo-EM these have already been used for 
automatic particle picking and map improvement). And they all need to 
worry about validating models based on predicted models.


Having said that, I think there is also a need for specialised, 
method-specific meetings, but the two types of meeting are not 
mutually exclusive.


My 2 öre,

--Gerard



On Mon, 30 Jan 2023, Alexandre Ourjoumtsev wrote:


Hi, everybody, hi, Nukri and Pavel !

I fully agree with Pavel that, if the speakers are not exceptional, 
if they are (as usually) concentrated on their specific and narrow 
problems, cross-discipline meetings make us lost quite fast, they are 
annoying and useless. Richard Feynmann had the same experience, 
according to his books :-)


At such meetings, people need to have a common point. However, it may 
be a point different from the SUBJECT of the research. This may be 
common TOOLS. And this indeed may lead to new ideas and results, 
maybe great ones.


There is a many-years positive experience of such meetings in 
Pushchino in 80ths (both of you know this place; for other readers of 
this post - this was indeed a great place !). Closer to our 
community, as I remember, Paul Adams and John Spence organized such 
kind of meetings about 20 years ago in US. I guess I know practical 
results from both these groups of meetings. Some Crystallographic 
Computing Schools also try to act a little bit "around the tools".


Why do not we think specifically in THIS direction (which is actually 
what Nukri said, right? and somehow not so far from the previous GRC?) ?

This is hard but feasible. But indeed hard :-(

Best regards to everybody,
and many thanks to James for raising the problem !

Sacha Urzhumtsev

- Le 30 Jan 23, à 2:38, Nukri Sanishvili  a 
écrit :



Hi Pavel,
Your description of the current status is exactly correct. And 
that's exactly
what I am proposing to change or, more accurately, try to change. By 
seeking
out and bringing together people who do complementary and 
collaborative work,

so they can set an example for others.
This, of course, isn't meant in place of more narrowly defined 
topical meetings

and conferences but to be in addition to those.
James asked the community if we had new ideas and this is a new-ish 
approach I

was suggesting.
Don't get me wrong - I myself will happily continue my efforts in 
more narrowly

defined meetings.
Best wishes,
Nukri


On Sun, Jan 29, 2023 at 6:44 PM Pavel Afonine < [ 
mailto:pafon...@gmail.com |

pafon...@gmail.com ] > wrote:



Nukri,


IMO, the idea of cross-discipline meetings is great conceptually, 
at least for

reasons you pointed out, but utopical in practice. When we attend our
field-specific meetings we meet colleagues we know, we talk to 
collaborators
from the past or find new ones, we have things in common that we 
can talk about
to forge something new, we meet authors of papers we were excited 
to read, and

so on, and so on.
I once attended a meeting of some chemistry society, well, which is 
not too far
from what we are doing, really, as interpreting atomic models is 
essentially
putting your chemistry knowledge into production. And, at that 
meeting I felt

like I'm alone in a dark forest.
Now, I imagine, if you bring two (or more) groups of people to your 
meeting from
two different domains, well, I guess you will end up having two 
bubbles of

people clustered by their field of interest.


Same disclaimer goes here as yours -- no offence to any one, just 
thinking out

loud...



All the best!
Pavel


On Sun, Jan 29, 2023 at 6:09 AM Nukri Sanishvili < [ 
mailto:sannu...@gmail.com |

sannu...@gmail.com ] > wrote:



Hi James,
This meeting has indeed been one of the best ones by its format, 
content, and
atmosphere. Many thanks to all the organizers and attendees of the 
past.
Nevertheless, it is not surprising that it was cancelled, given 
the trends in
structural biology research. Straightforward evolutionary pressure 

Re: [ccp4bb] Future Diffraction Methods

[Frank von Delft]

Shoot... that sucks.

Yes, we do need something!

"Structural Biology Methods"?


More interesting question:  does it need the GRC to host?  What about 
reimagining the CCP4 study weekend - the question keeps coming up there 
anyway.


That's one for CCP4 WG1 to discuss - they're meeting straight after New 
Year, so maybe James, you and Ivo should hop on a zoom and kick the idea 
around.


Frank



On 16/12/2022 22:10, James Holton wrote:
I want to thank everyone who attended the 2022 Gordon Research 
Conference and Gordon Research Seminar on Diffraction Methods in 
Structural Biology, as well as all those who contributed to these 
great gatherings in the past.  It was an outstanding meeting if I do 
say so myself. Not just because it had been so long without in-person 
interaction, not just because we had zero covid cases (which I see as 
no small feat of Mind over Virus), but because of this amazing 
community. It is rare in this world to have such a strong spirit of 
collaboration, camaraderie and openness in undertakings as high-impact 
as this. Surmounting the barriers to atomic-detail imaging of 
biological systems has never been more exciting and more relevant.  I 
am proud to be a part of it, and honored to have served as Chair.


It is therefore with heavy heart that I report to this community that 
I was the last Chair of the Diffraction Methods GRC.


The GRC Conference Evaluation Committee 
(https://www.grc.org/about/conference-evaluation-committee/) voted 
this year to discontinue the Diffraction Methods GRC and GRS. This 
ends a 46-year tradition that I feel played a vital, and vibrant role 
in the work of the people who answer questions on this BB. The reason 
given was insufficient attendance.  All other metrics, such as 
evaluation surveys and demographics were very strong. I have tried to 
appeal, but I'm told the vote was unanimous and final. I understand 
that like so many conference organizing bodies the GRC is having to 
make tough financial decisions. I must say I disagree with this one, 
but it was not my decision to make.


Many of the past and elected Chairs have been gathering and discussing 
how to replace the Diffraction Methods GRC/GRS going forward. Many 
great ideas, advice and perspectives have been provided, but that is a 
select group. I feel it is now time to open up this discussion to the 
broader community of structural methods developers and practitioners. 
There are some important questions to ask:


* How do we define this community?
        Yes, many of us do cryoEM too, but is that one methods 
meeting? or two?

* Does this community need a new diffraction methods meeting?
        As in one meeting or zero?
* Should we merge with an existing meeting?
    It would make logistics easier, but a typical GRC has 22 hours 
of in-depth presentations over 5 days.  The GRS is 7 hours over 2 
days. As Chair, I found that was not nearly enough.

* Where do you think structural methods are going?
        I think I know, but I may be biased.
* Should the name change?
        From 1976 to 2000, it was "Diffraction Methods in Molecular 
Biology". The word "diffraction", BTW, comes from the Latin for 
"shattering of rays", and originally used to describe the iridescence 
of bird feathers. That's spectroscopy!

How about:
 "Structural Methods for the Departing of Rays"

I'm sure there are many more questions, and better suggestions.  I 
look forward to enlightening discussions!  GRCs have always been about 
discussion, and I hope to keep that tradition alive in this community.


-James Holton
MAD Scientist



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Re: [ccp4bb] Another folding AI

[Frank von Delft]

Great, now we have two random number generators.


On 03/11/2022 12:10, David J. Schuller wrote:

https://www.biorxiv.org/content/10.1101/2022.07.20.500902v2


Evolutionary-scale prediction of atomic level protein structure with a 
language model 


doi: https://doi.org/10.1101/2022.07.20.500902


Abstract

Artificial intelligence has the potential to open insight into the 
structure of proteins at the scale of evolution. It has only recently 
been possible to extend protein structure prediction to two hundred 
million cataloged proteins. Characterizing the structures of the 
exponentially growing billions of protein sequences revealed by large 
scale gene sequencing experiments would necessitate a breakthrough in 
the speed of folding. Here we show that direct inference of structure 
from primary sequence using a large language model enables an order of 
magnitude speed-up in high resolution structure prediction. Leveraging 
the insight that language models learn evolutionary patterns across 
millions of sequences, we train models up to 15B parameters, the 
largest language model of proteins to date. As the language models are 
scaled they learn information that enables prediction of the 
three-dimensional structure of a protein at the resolution of 
individual atoms. This results in prediction that is up to 60x faster 
than state-of-the-art while maintaining resolution and accuracy. 
Building on this, we present the ESM Metagenomic Atlas. This is the 
first large-scale structural characterization of metagenomic proteins, 
with more than 617 million structures. The atlas reveals more than 225 
million high confidence predictions, including millions whose 
structures are novel in comparison with experimentally determined 
structures, giving an unprecedented view into the vast breadth and 
diversity of the structures of some of the least understood proteins 
on earth.



  Competing Interest Statement

The authors have declared no competing interest.



===
 All Things Serve the Beam
 ===
 David J. Schuller
 modern man in a post-modern world
 MacCHESS, Cornell University
schul...@cornell.edu



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Re: [ccp4bb] PAIREF, Anisotropy and STARANISO

[Frank von Delft]

Gerard, that's fascinating, thanks for the explanation.

I conclude in summary:  nobody (including you) yet knows whether any 
refinement program properly extracts the high-resolution signal when 
there's anisotropy.


My (similar) question a few days ago was: /"Is that because of the 
practicalities of implementing the numerical methods, or because of 
something fundamental about the refinement formalism?"//

/
I think you say below that the problem is (might be?) that the error 
models and corrections assume isotropic behaviour.


*So if that doesn't work, shouldn't the error models instead be derived 
from the statistics of local reciprocal space?  As you do in STARANISO 
(from memory).**

*
Frank







On 04/10/2022 17:01, Gerard Bricogne wrote:

Dear all,

  First of all, apologies for breaking the threads entitled "PAIREF -
Warning - not enough free reflections in resolution bin" and "Anisotropy" by
merging them into a new one, but it somehow felt rather against nature to
keep them separate.

  Since the early days of the availability of STARANISO [1] (the actual
starting year for the Web server [2] was 2016), we had a hunch that much of
what was happening in the PAIREF procedure might simply be the detection of
the existence of significant data beyond an initially chosen resolution
cut-off not only as a result of an excessively conservative criterion having
been applied in that initial choice, but as a consequence of anisotropy in
the data. The latter would give rise to different diffraction limits in
different directions, and the choice of a single value for "the resolution"
at which the data were cut off would necessarily yield a compromise value
between the best and the worse diffraction limits. This would imply that
significant data would be excluded in the best diffracting directions, that
would subsequently drive PAIREF towards increasing the estimated resolution
compared to its compromise value.

  This "hunch" was validated by a detailed comparison carried out on the
exact same examples that are considered in the 2020 paper by Maly et al.,
that is summarised in the attached PDF. In other words, whenever anisotropy
is present in the data, PAIREF will tend to indicate a higher value for an
isotropic cut-off than would have been estimated for the initial dataset.
The problem with taking the PAIREF result as the final answer is that the
higher cut-off it indicates is applied *isotropically*. The inclusion of the
significant data thus reclaimed is therefore unavoidably accompanied by that
of noisy data in the worst diffracting direction(s), resulting in alarmingly
poor statistics in the outermost shell (as pointed out in Eleanor's message)
that may cast doubts on the usefulness of the procedure. This consideration
was the basis of the rationale for implementing an *anisotropic* cut-off
surface in STARANISO, so that one could thus reclaim the significant data in
the best-diffracting direction(s) while avoiding the simultaneous inclusion
of the pure-noise measurements in the worse one(s). While this is clearly
and extensively explained in the documentation provided on the STARANISO
server [2], it seems to be far from having been assimilated. Of course this
would be perfect material for a publication, but life is somehow too short,
and our to-do list has remained too long, to leave us room for spending the
necessary time to go through the process of putting a paper together. The
truly important matter is to get our picture in front of the user community.

  Now that the combined topics of PAIREF and anisotropy are being brought
to the foreground of the community's attention, this seems like the perfect
opportunity to present our analysis and position: what PAIREF achieves in
terms of an upward revision of an initial isotropic resolution cut-off is
likely to be achieved more straightforwardly by submitting the same data to
the STARANISO server (or using it within autoPROC [3]); and the STARANISO
output will have the advantage of being devoid of the large extra amount of
purely noisy, uninformative data that are retained in the output from PAIREF
according to its revised isotropic cut-off.

  We would very much welcome feedback on this position: indeed we would
like to *crowd-source* the validation (or refutation) of this conclusion. In
our view, continuing to use the PAIREF procedure to revise an isotropic
resolution cut off misses the point about the consequences of anisotropy.
The only sensible use of a PAIREF-like procedure would be to adjust the
cut-off threshold for the local average of I/sig(I) in STARANISO, whose
default value is currently 1.2 but can be reset by the user through the Web
server's GUI. We occasionally see datasets of very high quality for which
the CC_1/2 value in the outermost shell stays above 0.6 or even 0.7, and it
is quite plausible that further useful data could be rescued if the local
I/sig(I) cut-off threshold were lowered below 1.2.

  

Re: [ccp4bb] issues running PANDDA with anisotropic data

[Frank von Delft]

Hi Charlie - that's quite a technical question, so I suggest you ask the 
question on the xchembb (use The Google to find it), in case someone has 
that script to hand.


(But if you need to do any scripting, chances are you'll need to spend a 
few days on the Google anyway, even if someone can send you an example.  
The good news is that bash is really simple.)


The PanDDA algorithm does not work if maps are not carefully coordinated 
around which reflections are included, especially at low resolution - 
though I'm not aware that anybody has carefully analysed what happens 
with very anisotropic data.


Frank




On 27/09/2022 10:26, Nichols, Charlie wrote:


Dear All,

Having some difficulty running PANDDA with a large batch of structures 
with significantly anisotropic data:


 1. We have to use Autoproc / Staraniso processing for all datasets.
 2. The default Dimple (Refmac) pipeline gives weird maps with large
areas of -ve density for no apparent reason which then really mess
up the difference-difference map calculations critical for PANDDA
success.
 3. Test refinements showed that Buster refinement of the Staraniso
output gave better maps which we hope will improve the
interpretability of the PANDDA maps.
 4. Pipedream run on 1000 datasets but PANDDA fails as it requires
complete datasets with any missing reflections filled in from Fcalc
 5. Unfortunately PANDDA does not have the correct structure factor
names in the check list – It looks for these pairs: FWT and PHWT,
2FOFCWT_fill and PH2FOFCWT_fill and 2FOFCWT and PH2FOFCWT
 6. Pipedeam/Buster outputs iso and aniso filled data so it has
2FOFCWT-iso-fill/PH2FOFCWT_iso-fill and
2FOFCWT-aniso-fill/PH2FOFCWT_aniso-fill which PANDDA does not see
so crashes out.

My scripting is not great so I wondered if anyone could hep me with a 
short script to recursively look for ‘refine.mtz’ within 
subdirectories from the top-level ‘model-building’ directory and then 
run CAD to change the column names from 2FOFCWT-iso-fill and 
PH2FOFCWT_iso-fill to 2FOFCWT_fill and PH2FOFCWT_fill so PANDDA can 
‘see’ the correct data columns


NB: output .mtz name must still be ‘refine.mtz’ as PANDDA only checks 
the top-level directory for each refinement and ‘pipedream.mtz’ 
symlinks pointing to ‘pipedream/pipedreamDir/refine/refine.mtz’ are 
already in place.


Full path:

model_building/target_x/pipedream/pipedreamDir/refine/refine.mtz

Thanks for your help,

Take care, Charlie.




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[ccp4bb] Recruiting XChem postdocs for antivirals

[Frank von Delft]

Hello - with the Moonshot <https://postera.ai/moonshot/> going better 
than we dreamed 
<https://dndi.org/research-development/portfolio/covid-moonshot/>, 
helping the ASAP consortium <https://asapdiscovery.org/> become 
<https://www.diamond.ac.uk/Home/News/LatestNews/2022/19-05-22.html> one 
of the NIH/NIAID's AViDD Centers 
<https://www.nih.gov/news-events/news-releases/nih-announces-antiviral-drug-development-awards>, 
we are recruiting several postdocs to Diamond's XChem team 
<https://www.diamond.ac.uk/Instruments/Mx/Fragment-Screening.html>, to 
work in two large international consortia, the other being AViDD-funded 
READDi 
<https://sph.unc.edu/sph-news/unc-chapel-hill-receives-65m-from-nih-for-antiviral-drug-development-center/>.


They will help run the crystallography to drive the development of new 
antivirals; to generate a huge, high-quality open dataset to accelerate 
community-wide efforts on computational methods; and to push and harden 
new methodologies.


Crystallographers that program or do medchem -- or programmers or 
medchemists that do crystallography -- might find the posts particularly 
interesting.  It will include close work with my and other groups at 
Oxford's Centre for Medicines Discovery <https://www.cmd.ox.ac.uk/> (CMD).


Vacancy link is here 
<https://vacancies.diamond.ac.uk/vacancy/postdoctoral-research-associate-antiviral-xchem-496546.html>; 
closing date is Sept 4th.  Feel free to email me with questions.


Frank



Prof Frank von Delft
Professor for Structural Chemical Biology
Principal Beamline Scientist: I04-1/XChem
Diamond Light Source
+44 1235 778997 (office: M,T,T)

Principal Investigator: Protein Crystallography
Centre for Medicines Discovery
Oxford University
Biochemistry Building, South Parks Road, OX1 3QU
+44 1865 617583 (office: W,F)
+44 7471 026103 (mobile)




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Re: [ccp4bb] Yes, there are now 214 *million* structures in the AlphaFold Protein Structure Database

[Frank von Delft]

Gerard, Sameer - that is highly impressive indeed


About that Editorial (nice read!), it frames these developments as a 
"crisis" that heralds "the end of structural biology" - or at the very 
least, you're responding to people having said that.  I remain puzzled 
that such stuff receive any editorial oxygen - to me it's like saying 
that that higher flux and automation at synchrotrons threaten 
crystallography.  Or something.  AlphaFold is just another tool - a 
sensationally powerful one, of course, but it doesn't Do Science.


Unless there have been noises from Funders - in which case we do need a 
calls to arms, to scream some sense into them.


Btw, for whoever missed it, AlphaFold models are as accurate as 3.5A 
structures: 
https://twitter.com/LindorffLarsen/status/1527410977213403147. So 
they're amazing, but Real Crystallographers know the experimental 
distance between 3.5 and the 2.2 needed for structure-supported ligand 
design, to name just one.


Frank



On 28/07/2022 16:19, Gerard Kleywegt wrote:

Hi all,

I thought Sameer was burying the lead a tad in his message... :-) So, 
for those of you who -like me- are not on social media:


==> As of today, the AlphaFold Protein Structure Database contains 214 
million models predicted with AlphaFold, covering almost all of 
UniProt. <==


So, if your favourite protein was not available in the database before 
today, it's worth checking in again at 
https://www.alphafold.ebi.ac.uk/ now.


See also:

- EMBL-EBI press release: 
https://www.ebi.ac.uk/about/news/technology-and-innovation/alphafold-200-million/


- Nature news: https://www.nature.com/articles/d41586-022-02083-2

- IUCr J guest editorial about the potential impact of all this on 
structural biologists (shameless plug): 
https://journals.iucr.org/m/issues/2022/04/00/me6185/index.html



Best wishes,

--Gerard





On Thu, 28 Jul 2022, Sameer Velankar wrote:


Dear All,

You may have seen our announcement today about expanding the 
AlphaFold Protein Structure Database to 214M predicted models. To 
enable this expansion, we’ve updated the Predicted Aligned Error 
(PAE) JSON format to make it compact (about 4x smaller):


The PAE JSON numbers are now rounded to the closest integer, giving 
~75% compressed size reduction. The integer resolution is sufficient 
for analytical purposes.
The indices are not stored anymore since we store the full 2D PAE 
matrix rather than a sparse one, giving ~4% compressed size reduction.
The “distances” field has been renamed to “predicted_aligned_error” 
and is now stored as a 2D array of shape (num_res, num_res) rather 
than a 1D array. We renamed the field on purpose so that existing 
code breaks rather than potentially silently returning wrong values.


For a protein of length num_res, the PAE JSON file has now the 
following format:


[{
 "predicted_aligned_error": [[0, 1, 4, 7, 9, ...], ...],  # Shape: 
(num_res, num_res).

 "max_predicted_aligned_error": 31.75  # Scalar.
}]

The fields in the JSON file are:
predicted_aligned_error: The PAE value of the residue pair, rounded 
to the closest integer. For PAE value on position (i, j), i is the 
residue on which the structure is aligned for the predicted error, j 
is the residue on which the error is predicted.
max_predicted_aligned_error: A number that denotes the largest 
possible unrounded value of PAE that could occur in the PAE array. 
The smallest possible value of PAE is 0.


The updated PAE format is only available from the AlphaFold Protein 
Structure Database. The PAE format from the AlphaFold Colab notebook 
is not updated.


If you require support with this change, please email 
alphaf...@deepmind.com  and they may 
be able to assist.


Best Wishes,

Sameer Velankar


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Best wishes,

--Gerard

**
   Gerard J. Kleywegt

  http://xray.bmc.uu.se/gerard   mailto:ger...@xray.bmc.uu.se
**
   The opinions in this message are fictional.  Any similarity
   to actual opinions, living or dead, is purely coincidental.
**
   Little known gastromathematical curiosity: let "z" be the
   radius and "a" the thickness of a pizza. Then the volume
    of that pizza is equal to pi*z*z*a !
**



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Re: [ccp4bb] open review?

[Frank von Delft]

I suspect funders will worry about it becoming even harder to find 
reviewers - they're already hard to flush out, if I'm not mistaken, and 
might become even more reclusive if they run the risk of being pilloried 
in public.


If that sounds theoretical:  even in this community, for all its 
collegiality and friendliness, we pillory one another in public and 
print just about our /data/.


Frank


On 23/06/2022 02:08, James Holton wrote:

Greetings all,

I'd like to ask a question that I expect might generate some spirited 
discussion.


We have seen recently a groundswell of support for openness and 
transparency in peer review. Not only are pre-prints popular, but we 
are also seeing reviewer comments getting published along with the 
papers themselves. Sometimes even signed by the reviewers, who would 
have traditionally remained anonymous.


My question is: why don't we also do this for grant proposals?

I know this is not the norm. However, after thinking about it, why 
wouldn't we want the process of how funding is awarded in science to 
be at least as transparent as the process of publishing the results? 
Not that the current process isn't transparent, but it could be more 
so. What if applications, and their reviewer comments, were made 
public? Perhaps after an embargo period? There could be great benefits 
here. New investigators especially, would have a much clearer picture 
of format, audience, context and convention. I expect unsuccessful 
applications might be even more valuable than successful ones. And 
yet, in reality, those old proposals and especially the comments 
almost never see the light of day. Monumental amounts of work goes 
into them, on both sides, but then get tucked away into the darkest 
corners of our hard drives.


So, 2nd question is: would you do it? Would you upload your 
application into the public domain for all to see? What about the 
reviewer comments? If not, why not?  Afraid people will steal your 
ideas? Well, once something is public, its pretty clear who got the 
idea first.


3rd question: what if the service were semi-private? and you got to 
get comments on your proposal before submitting it to your funding 
agency? Would that be helpful? What if in exchange for that service 
you had to review 2-3 other applications?  Would that be worth it?


Or, perhaps, I'm being far too naiive about all this. For all I know 
there are some rules against doing this I'm not aware of. Either way, 
I'm interested in what this community thinks. Please share your 
views!  On- or off-list is fine.


-James Holton
MAD Scientist



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[ccp4bb] Doctoral studentship: Fragments to Field

[Frank von Delft]

Dear all

I have a new studentship open, "Fragment to Field", to work on the 
details of how to use fragment approaches for crop science.


Please circulate to any students you're aware are interested in this 
kind of thing.



Webpage is here: 
https://www.ndm.ox.ac.uk/study/dphil-themes?project=fragment-to-field


Deadline is January 7th (quite soon, sorry).


Frank





*Theme Overview*

This is an EPSRC-funded iCASE project, both home, and overseas 
candidates are welcome to apply, closing date to be considered for 
funding is Friday 7 January 2022.


Herbicide resistance has become a major worldwide problem which is 
affecting humanity's ability to cost-effectively feed itself and this is 
particularly felt in developing nations. The identification and 
development of novel and safe herbicides is required to control weeds 
that have evolved resistance to the existing herbicides. Fragment-based 
design is a very effective way of finding exciting new starting points 
for inhibitors and is potentially well suited to herbicide research 
where many key plant targets are soluble. A significant challenge of 
this approach is the conversion of hits to a potent inhibitor as it is 
slow and expensive. Therefore, the aim of this project is to develop 
workflows and methods to improve the efficiency of this step.


The key research question that will be addressed during the course of 
the studentship are:


1. Does crystal-based fragment screening accelerate discovery of
   plant-targeting chemical matter?
2. What strategies and rules are appropriate for plant-targeting
   compound design?
3. How can these strategies be incorporated into workflows and
   algorithms for compound design?
4. On what principles should plant-based protein targets be selected
   for these strategies?


*Training opportunities*

We offer a DPhil position as part of a collaboration between the Centre 
for Medicines Discovery and Syngenta. The project entails excellent 
training in a wealth of scientific cutting-edge techniques, such as 
molecular biology and protein biochemistry in an industry-leading 
automated facility at the CMD, protein crystallography and small-angle 
X-ray scattering at the Diamond Light Source (DLS), single-particle 
Cryo-Electron Microscopy, structure-based fragment screening, and 
Artificial Intelligence-based fragment progression approaches in 
small-molecule drug discovery. Additionally, the PhD candidate will 
receive training in biophysical techniques such as Isothermal Titration 
Calorimetry, Surface Plasmon Resonance, Biolayer Interferometry, and 
Microscale Thermophoresis among others, all available at CMD facilities. 
As part of this PhD studentship, the candidate will have the opportunity 
to spend 3 months at Syngenta, a unique opportunity to get an insight 
into industrial research and to build a professional network.




Prof Frank von Delft
Professor for Structural Chemical Biology
Principal Beamline Scientist: I04-1/XChem
Diamond Light Source
+44 1235 778997 (office: M,T,T)

Principal Investigator: Protein Crystallography
Centre for Medicines Discovery
Oxford University
+44 1865 617583 (office: W,F)
+44 7471 026103 (mobile)



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Re: [ccp4bb] High-order oligomers vs robust crystals - references?

[Frank von Delft]

Dear all, thanks all for the several references you emailed around.

Here's a summary:

A Suite of Engineered GFP Molecules for Oligomeric Scaffolding
https://www.sciencedirect.com/science/article/pii/S0969212615002890

Dimerization properties of the RpBphP2 chromophore-binding domain 
crystallized by homologue-directed mutagenesis

https://pubmed.ncbi.nlm.nih.gov/22868772/

An approach to crystallizing proteins by synthetic symmetrization
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1637565/

Why protein crystals favour some space-groups over others
https://www.nature.com/articles/nsb1295-1062

Infinite Assembly of Folded Proteins in Evolution, Disease,and Engineering
https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.201806092



James Holton duly challenged me, and here's my reply:

   JH: If I told you "no, that's not true", how would you go about
   proving me wrong?  What would that data look like?
   --
   FvD: Geezus, I don't know!   It's not me that hurled this brainfart
   around the grant funding agencies 20 years ago... That's why I asked
   the Social Brain.

   But my primary goal was to have something to stick into the
   introduction to a paper, so that has been achieved. Whether it's
   ethical to perpetuate a brainfart by citing other expressions of the
   brainfart is a reasonable question, but this one would rank quite
   low on the impact-of-transgression scale, methinks.


But Dhiraj's reply to my original question is a surely a better one:
/"Recently there were few articles where synthetic symmetrization was 
used to enhance the crystallizability. proteins used were MBP, lysozyme 
and GFP to name a few."//

/
It implies the weight-of-evidence is out there - hint to you 
enterprising students, looking for something *actually useful* to write 
a review about!


Frank



On 12/11/2021 14:52, Frank von Delft wrote:

Hello all

Two decades ago, I remember (!) much talk about a reason that 
bacterial proteins crystallize "more easily" is that they tend to come 
as oligomers (dimers and up), and that this internal symmetry made 
them happier to crystallize.


Did anybody ever publish hard evidence?  Or even, is there a primary 
citation for the idea?


Thanks
Frank



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[ccp4bb] 2021 Moonshot Webinar - 16 Dec 4pm GMT

[Frank von Delft]

Dear BB

It's been 20 months since we broadcast on this BB (and elsewhere) for 
help to develop a SARS-CoV-2 Mpro inhibitor from XChem fragments.  The 
thing is still going strong, and in the open, with funding up to clinic.


Please do sign up if you're interested in drug discovery and 
development, for a real-time in-depth look at how it's going.


Frank



 




 Hi Frank,


As we approach year end, the Moonshot team would love the chance to 
update you on our 2021 progress and 2022 plans in moving our 
open-science antiviral candidates closer to the clinic.


Come join us for our end of year webinar!

*Details*

 * Date: Thursday 16th December
 * Time: 4pm - 5:30pm GMT

Webinar Registration 
 




If you have any further questions, please reach out to _covid@postera.ai_


Looking forward to seeing you all,
PostEra, on behalf of the COVID Moonshot team



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[ccp4bb] High-order oligomers vs robust crystals - references?

[Frank von Delft]

Hello all

Two decades ago, I remember (!) much talk about a reason that bacterial 
proteins crystallize "more easily" is that they tend to come as 
oligomers (dimers and up), and that this internal symmetry made them 
happier to crystallize.


Did anybody ever publish hard evidence?  Or even, is there a primary 
citation for the idea?


Thanks
Frank



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Re: [ccp4bb] am I doing this right?

[Frank von Delft]

Thanks, I learnt two things now - one of which being that I'm credited 
with coining that word!  Stap me vittals...


If it's single photon events you're after, isn't it quantum statistics 
where you need to go find that prior?  (Or is that what you're doing in 
this thread - I wouldn't be able to tell.)


Also:  should the detectors change how they read out things, then? Just 
write out the events with timestamp, rather than dumping all pixels all 
the time into these arbitrary containers called "image". Or is that 
what's already happening in HDF5 (which I don't understand one bit, I 
should add).


Frank




On 17/10/2021 18:12, James Holton wrote:


Well Frank, I think it comes down to something I believe you were the 
first to call "dose slicing".


Like fine phi slicing, collecting a larger number of weaker images 
records the same photons, but with more information about the sample 
before it dies. In fine phi slicing the extra information allows you 
to do better background rejection, and in "dose slicing" the extra 
information is about radiation damage. We lose that information when 
we use longer exposures per image, and if you burn up the entire 
useful life of your crystal in one shot, then all information about 
how the spots decayed during the exposure is lost. Your data are also 
rather incomplete.


How much information is lost? Well, how much more disk space would be 
taken up, even after compression, if you collected only 1 photon per 
image?  And kept collecting all the way out to 30 MGy in dose? That's 
about 1 million photons (images) per cubic micron of crystal.  So, I'd 
say the amount of information lost is "quite a bit".


But what makes matters worse is that if you did collect this data set 
and preserved all information available from your crystal you'd have 
no way to process it. This is not because its impossible, its just 
that we don't have the software. Your only choice would be to go find 
images with the same "phi" value and add them together until you have 
enough photons/pixel to index it. Once you've got an indexing solution 
you can map every photon hit to a position in reciprocal space as well 
as give it a time/dose stamp. What do you do with that?  You can do 
zero-dose extrapolation, of course!  Damage-free data! Wouldn't that 
be nice. Or can you?  The data you will have in hand for each 
reciprocal-space pixel might look something like:
tic tic .. tic . tic ... tic tictic ... 
tictic.


So. Eight photons.  With time-of-arrival information.  How do you fit 
a straight line to that?  You could "bin" the data or do some kind of 
smoothing thing, but then you are losing information again. Perhaps 
also making ill-founded assumptions. You need error bars of some kind, 
and, better yet, the shape of the distribution implied by those error 
bars.


And all this makes me think somebody must have already done this. I'm 
willing to bet probably some time in the late 1700s to early 1800s. 
All we're really talking about here is augmenting maximum-likelihood 
estimation of an average value to maximum-likelihood estimation of a 
straight line. That is, slope and intercept, with sigmas on both. I 
suspect the proper approach is to first bring everything down to the 
exact information content of a single photon (or lack of a photon), 
and build up from there.  If you are lucky enough to have a large 
number of photons then linear regression will work, and you are back 
to Diederichs (2003). But when you're photon-starved the statistics of 
single photons become more and more important.  This led me to: is it 
k? or k+1 ?  When k=0 getting this wrong could introduce a factor of 
infinity.


So, perhaps the big "consequence of getting it wrong" is embarrassing 
myself by re-making a 200-year old mistake I am not currently aware 
of. I am confident a solution exists, but only recently started 
working on this.  So, I figured ... ask the world?


-James Holton
MAD Scientist


On 10/17/2021 1:51 AM, Frank Von Delft wrote:
James, I've been watching the thread with fascination, but also the 
confusion of wild ignorance. I've finally realised why.


What I've missed is: what exactly makes the question so important?  
I've understood what brought it up, if course, but not the 
consequence of getting it wrong.


Frank

Sent from tiny silly touch screen

*From:* James Holton 
*Sent:* Saturday, 16 October 2021 20:01
*To:* CCP4BB@JISCMAIL.AC.UK
*Subject:* Re: [ccp4bb] am I doing this right?

Thank you everyone for your thoughtful and thought-provoking responses!

But, I am starting to think I was not as clear as I could have been
about my question.  I am actually concerning myself with background, not
necessarily Bragg peaks.  With Bragg photons you want the sum, but for
background you want the averag

Re: [ccp4bb] am I doing this right?

[Frank Von Delft]

James, I've been watching the thread with fascination, but also the confusion 
of wild ignorance. I've finally realised why.

What I've missed is: what exactly makes the question so important?  I've 
understood what brought it up, if course, but not the consequence of getting it 
wrong.

Frank

Sent from tiny silly touch screen

From: James Holton 
Sent: Saturday, 16 October 2021 20:01
To: CCP4BB@JISCMAIL.AC.UK
Subject: Re: [ccp4bb] am I doing this right?

Thank you everyone for your thoughtful and thought-provoking responses!

But, I am starting to think I was not as clear as I could have been
about my question.  I am actually concerning myself with background, not
necessarily Bragg peaks.  With Bragg photons you want the sum, but for
background you want the average.

What I'm getting at is: how does one properly weight a zero-photon
observation when it comes time to combine it with others?  Hopefully
they are not all zero.  If they are, check your shutter.

So, ignoring Bragg photons for the moment (let us suppose it is a
systematic absence) what I am asking is: what is the variance, or,
better yet,what is the WEIGHT one should assign to the observation of
zero photons in a patch of 10x10 pixels?

In the absence of any prior knowledge this is a difficult question, but
a question we kind of need to answer if we want to properly measure data
from weak images.  So, what do we do?

Well, with the "I have no idea" uniform prior, it would seem that
expectation (Epix) and variance (Vpix) would be k+1 = 1 for each pixel,
and therefore the sum of Epix and Vpix over the 100 independent pixels is:

Epatch=Vpatch=100 photons

I know that seems weird to assume 100 photons should have hit when we
actually saw none, but consider what that zero-photon count, all by
itself, is really telling you:
a) Epix > 20 ? No way. That is "right out". Given we know its Poisson
distributed, and that background is flat, it is VERY unlikely you have E
that big when you saw zero. Cross all those E values off your list.
b) Epix=0 ? Well, that CAN be true, but other things are possible and
all of them are E>0. So, most likely E is not 0, but at least a little
bit higher.
c) Epix=1e-6 ?  Yeah, sure, why not?
d) Epix= -1e-6 ?  No. Don't be silly.
e) If I had to guess? Meh. 1 photon per pixel?  That would be k+1

I suppose my objection to E=V=0 is because V=0 implies infinite
confidence in the value of E, and that we don't have. Yes, it is true
that we are quite confident in the fact that we did not see any photons
this time, but the remember that E and V are the mean and variance that
you would see if you did a million experiments under the same
conditions. We are trying to guess those from what we've got. Just
because you've seen zero a hundred times doesn't mean the 101st
experiment won't give you a count.  If it does, then maybe Epatch=0.01
and Epix=0.0001?  But what do you do before you see your first photon?
All you can really do is bracket it.

But what if you come up with a better prior than "I have no idea" ?
Well, we do have other pixels on the detector, and presuming the
background is flat, or at least smooth, maybe the average counts/pixel
is a better prior?

So, let us consider an ideal detector with 1e6 independent pixels. Let
us further say that 1e5 background photons have hit that detector.  I
want to still ignore Bragg photons because those have a very different
prior distribution to the background.  Let us say we have masked off all
the Bragg areas.

The average overall background is then 0.1 photons/pixel. Let us assign
that to the prior probability Ppix = 0.1.  Now let us look again at that
patch of 10x10 pixels with zero counts on it.  We expected to see 10,
but got 0.  What are the odds of that?  Pretty remote.  Less than 1 in a
million.

I suspect in this situation where such an unlikely event has occurred it
should perhaps be given a variance larger than 100. Perhaps quite a bit
larger?  Subsequent "sigma-weighted" summation would then squash its
contribution down to effectively 0. So, relative to any other
observation with even a shred of merit it would have no impact. Giving
it V=0, however? That can't be right.

But what if Ppix=0.01 ?  Then we expect to see zero counts on our
100-pixel patch about 1/3 of the time. Same for 1-photon observations.
Giving these two kinds of observations the same weight seems more
sensible, given the prior.

Another prior might be to take the flux and sample thickness into
account.  Given the cross section of light elements the expected
photons/pixel on most any detector would be:

Ppix = 1.2e-5*flux*exposure*thickness*omega/Npixels
where:
Ppix = expected photons/pixel
Npixels = number of pixels on the detector
omega  = fraction of scattered photons that hit it (about 0.5)
thickness = thickness of sample and loop in microns
exposure = exposure time in seconds
flux = incident beam flux in photons/s
1.2e-5 = 1e-4 cm/um * 1.2 

[ccp4bb] XChem proposals: NEXT WEDS (Oct 6)

[Frank von Delft]

Hello all -

Reminder of the deadline *NEXT WEEK WEDNESDAY Oct 6 (5pm UK)* to apply 
for access to Diamond's XChem facility for April-Oct 2022.


(Same deadline as other Diamond access, in case you're wondering - it's 
2x per year.)


NOTE:  Diamond greatly welcomes BAG proposals, it makes everybody's 
lives massively simpler.
So if you are aware of colleagues that are close (whether 
geographically, organisationally or even scientifically), that also want 
to do XChem, please do reach out to them, and read the proposal 
instructions carefully.



The XChem webpage is here:
https://www.diamond.ac.uk/Instruments/Mx/Fragment-Screening/ 
<https://www.diamond.ac.uk/Instruments/Mx/Fragment-Screening/>


How to apply is here:
https://www.diamond.ac.uk/Instruments/Mx/Fragment-Screening/XChem-Applications.html 
<https://www.diamond.ac.uk/Instruments/Mx/Fragment-Screening/XChem-Applications.html>



Looking forward to your applications!
Frank


Prof. Frank von Delft
Professor for Structural Chemical Biology
Principal Beamline Scientist: I04-1/XChem
Diamond Light Source
+44 1235 778997 (o)
+44 7471 026103 (m)




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Re: [ccp4bb] AI papers in experimental macromolecular structure determination

[Frank von Delft]

Thanks Andrea for this!

One more for crystallization:

Ng JT., Dekker C., Kroemer M., Osborne M., von Delft F., (2014), Acta D, 
70, 2702 - 2718




On 03/08/2021 12:43, Thorn, Dr. Andrea wrote:


Dear colleagues,

I have compiled a list of papers that cover the application of 
AI/machine learning methods in single-crystal structure determination 
(mostly macromolecular crystallography) and single-particle Cryo-EM. 
The draft list is attached below.


If I missed any papers, please let me know. I will send the final list 
back here, for the benefit of all who are interested in the topic.


Best wishes,

Andrea.

__

General:

- Gopalakrishnan, V., Livingston, G., Hennessy, D., Buchanan, B. & 
Rosenberg, J. M. (2004). Acta Cryst D. 60, 1705–1716.


- Morris, R. J. (2004). Acta Cryst D. 60, 2133–2143.

Micrograph preparation:

- (2020). Journal of Structural Biology. 210, 107498.

Particle Picking:

- Sanchez-Garcia, R., Segura, J., Maluenda, D., Carazo, J. M. & 
Sorzano, C. O. S. (2018). IUCrJ. 5, 854–865.


- Al-Azzawi, A., Ouadou, A., Tanner, J. J. & Cheng, J. (2019). BMC 
Bioinformatics. 20, 1–26.


- George, B., Assaiya, A., Roy, R. J., Kembhavi, A., Chauhan, R., 
Paul, G., Kumar, J. & Philip, N. S. (2021). Commun Biol. 4, 1–12.


- Lata, K. R., Penczek, P. & Frank, J. (1995). Ultramicroscopy. 58, 
381–391.


- Nguyen, N. P., Ersoy, I., Gotberg, J., Bunyak, F. & White, T. A. 
(2021). BMC Bioinformatics. 22, 1–28.


- Wang, F., Gong, H., Liu, G., Li, M., Yan, C., Xia, T., Li, X. & 
Zeng, J. (2016). Journal of Structural Biology. 195, 325–336.


- Wong, H. C., Chen, J., Mouche, F., Rouiller, I. & Bern, M. (2004). 
Journal of Structural Biology. 145, 157–167.


Motion description in Cryo-EM:

- Matsumoto, S., Ishida, S., Araki, M., Kato, T., Terayama, K. & 
Okuno, Y. (2021). Nat Mach Intell. 3, 153–160.


- Zhong, E. D., Bepler, T., Berger, B. & Davis, J. H. (2021). Nat 
Methods. 18, 176–185.


Local resolution:

- Avramov, T. K., Vyenielo, D., Gomez-Blanco, J., Adinarayanan, S., 
Vargas, J. & Si, D. (2019). Molecules. 24, 1181.


- Ramírez-Aportela, E., Mota, J., Conesa, P., Carazo, J. M. & Sorzano, 
C. O. S. (2019). IUCrJ. 6, 1054–1063.


- (2021). QAEmap: A Novel Local Quality Assessment Method for Protein 
Crystal Structures Using Machine Learning.


Map post-processing:

- Sanchez-Garcia, R., Gomez-Blanco, J., Cuervo, A., Carazo, J. M., 
Sorzano, C. O. S. & Vargas, J. (2020). BioRxiv. 2020.06.12.148296.


Secondary structure assignment in map:

- Subramaniya, S. R. M. V., Terashi, G. & Kihara, D. (2019). Nat 
Methods. 16, 911–917.


- Li, R., Si, D., Zeng, T., Ji, S. & He, J. (2016). 2016 IEEE 
International Conference on Bioinformatics and Biomedicine (BIBM), 
Vol. pp. 41–46.


- Si, D., Ji, S., Nasr, K. A. & He, J. (2012). Biopolymers. 97, 698–708.

- He, J. & Huang, S.-Y. Brief Bioinform.

- Lyu, Z., Wang, Z., Luo, F., Shuai, J. & Huang, Y. (2021). Frontiers 
in Bioengineering and Biotechnology. 9,.


- Mostosi, P., Schindelin, H., Kollmannsberger, P. & Thorn, A. (2020). 
Angewandte Chemie International Edition.


Automatic structure building:

- Alnabati, E. & Kihara, D. (2020). Molecules. 25, 82.

- Si, D., Moritz, S. A., Pfab, J., Hou, J., Cao, R., Wang, L., Wu, T. 
& Cheng, J. (2020). Sci Rep. 10, 1–22.


- Moritz, S. A., Pfab, J., Wu, T., Hou, J., Cheng, J., Cao, R., Wang, 
L. & Si, D. (2019).


- Chojnowski, G., Pereira, J. & Lamzin, V. S. (2019). Acta Cryst D. 
75, 753–763.


Crystallization:

- Liu, R., Freund, Y. & Spraggon, G. (2008). Acta Cryst D. 64, 1187–1195.

- (2004). Methods. 34, 390–407.

- Bruno, A. E., Charbonneau, P., Newman, J., Snell, E. H., So, D. R., 
Vanhoucke, V., Watkins, C. J., Williams, S. & Wilson, J. (2018). PLOS 
ONE. 13, e0198883.


Crystal centering:

- Ito, S., Ueno, G. & Yamamoto, M. (2019). J Synchrotron Rad. 26, 
1361–1366.


- Crystal centering using deep learning in X-ray crystallography.

- Elbasir, A., Moovarkumudalvan, B., Kunji, K., Kolatkar, P. R., Mall, 
R. & Bensmail, H. (2019). Bioinformatics. 35, 2216–2225.


Diffraction image analysis:

- Czyzewski, A., Krawiec, F., Brzezinski, D., Porebski, P. J. & Minor, 
W. (2021). Expert Systems with Applications. 174, 114740.


Peak search in serial crystallography:

Ke, T.-W., Brewster, A. S., Yu, S. X., Ushizima, D., Yang, C. & 
Sauter, N. K. (2018). J Synchrotron Rad. 25, 655–670.


Space group assignment from diffraction image (small molecules):

Aguiar, J. A., Gong, M. L., Unocic, R. R., Tasdizen, T. & Miller, B. 
D. (2019). Science Advances. 5, eaaw1949.


Data quality assessment in MX:

- Vollmar, M., Parkhurst, J. M., Jaques, D., Baslé, A., Murshudov, G. 
N., Waterman, D. G. & Evans, G. (2020). IUCrJ. 7, 342–354.


Ligand recognition:

Kowiel, M., Brzezinski, D., Porebski, P. J., Shabalin, I. G., 
Jaskolski, M. & Minor, W. (2019). Bioinformatics. 35, 452–461.


Prediction of missing atoms in small molecular structures:

Thomas, N., Smidt, T., Kearnes, S., Yang, L., Li, L., Kohlhoff, K. & 
Riley, P. 

Re: [ccp4bb] pictures in emails

[Frank von Delft]

Ahem.  Ed, Tim - the 90s called, they want want their disk space and 
email clients back.


As a co-perpertrator of vast volumes of detector data, and religious 
proponent of text /formatting/ as inseparable part part the message, I 
disagree that in the year 2021, your suggestion still conforms to 
netiquette.


In case anybody was left with the impression that Tim and Ed's view was 
universal.


frank







On 19/07/2021 10:26, Tim Gruene wrote:

Hi Ed, dear ccp4bbs

I fully support your email!

Most email clients have a tick box to include a plain text version in
addition of the html-version in their preferences.

Reading plain text emails instead of the html-version (which is also an
available option for most email clients) is a very effective barrier
against spam. People should take this into account, considering the
global rise of ransomware attacks, with serious consequences to some
large institutions and companies.

It has always been good netiquette to at least include a text-version
of your email.

Cheers,
Tim

On Sun, 18 Jul 2021 11:17:26 -0400 Edward Berry 
wrote:


Two suggestions for people sending pictures of electron density to
the BB:

1. Reduce the size of the pictures-
The two pictures in yesterday's email appear nice and small in my
email client, but still illustrate what is being described. However
they are actually 4032x3024 and 2040x1458 pixels, making for rather
large emails. All that extra resolution is wasted unless the user
opens the image directly ("view image"), and in any case is
completely unnecessary for the point being made. I think about
600x600 pixels is plenty for almost anything you want to show in
electron density. This does not require manipulation in photoshop or
such- just reduce the size of the graphics window and take a
screenshot of that window.

2. send the picture as an attachment rather than inline. That way it
won't be included in all the replies. Or if the people replying could
find some way to exclude pictures or formt the reply as plain-text,
that would help.

(No, I'm not receiving these emails via 1200 baud modem- but I like
to save the messages for future reference. If the trend continues
toward high-resolution inline screenshots, that will take a
significant amount of disk space. And yes, I know there is an
archive.) eab



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[ccp4bb] XChem recruiting: Beamline Scientist

[Frank von Delft]

Hello all

We're recruiting a Beamline Scientist to the XChem facility at Diamond;  
the advert and details are below:


If you're wondering if it's for you:  the best ways to make a guaranteed 
impact in science is (a) to teach lots of smart young people and/or (b) 
work at a facility that accelerates others' science.


At Diamond (and XChem) you get to do both - and you get to not only work 
with but help develop the most astonishing technology. Geek-heaven, is 
what I call it.


https://vacancies.diamond.ac.uk/vacancy/beamline-scientist-xchem-448943.html 



Frank



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Re: [ccp4bb] Arcimboldo

[Frank von Delft]

That paper is jaw-dropping...


On 03/07/2021 10:33, Randy John Read wrote:

If there isn’t already a suitable model, this looks like a good opportunity to try 
out the powerful new RoseTTAFold deep learning algorithm by Minkyung Baek in David 
Baker’s lab.  It can be used through the Robetta server 
(http://robetta.bakerlab.org, choose Structure Prediction->Submit and then 
choose the RoseTTAFold option).  It’s already been used to solve a number of 
unsolved structures, including the ones discussed in a paper on the algorithm 
(https://www.biorxiv.org/content/10.1101/2021.06.14.448402v1) and others I’ve 
heard of through the grapevine.

Best wishes,

Randy


On 2 Jul 2021, at 12:52, Eleanor Dodson 
<176a9d5ebad7-dmarc-requ...@jiscmail.ac.uk> wrote:

Yes - nothing very significant in the self rotation list of peaks..
Is the resolution really 2.6A though - if so it will be very difficult to find 
a single helix which would be quite a small fraction of 70x2 residues Iwould 
think..
Is there no suitable model?
Eleabor

On Fri, 2 Jul 2021 at 12:45, leo john  wrote:
Thank you all.

I have tried both space groups. I am attaching the required file.

Cheers
John

On Fri, Jul 2, 2021 at 12:40 PM Eleanor Dodson  
wrote:
I presume you have tested both P41 and P43 space groups?
It is a bit hard to check peak heights in the self rotation. Could you attach 
the molrep output - I think it is called xxxmolrep.doc.txt in the
job directory..
Eleanor


On Fri, 2 Jul 2021 at 12:33, leo john  wrote:
Hi Group;

I have collected data at approximately 2 Ang and automated softwares at Diamond 
have processed it in spacegroup P41.
My peptide is 70 residues long with 3 helices of minimum 17 residues in it. 
According to Mat. Coeff. there are 2 molecules. I am also attaching the 
self-rotation function output map (please give some opinion on it also i.e 
number of molecules, symmetry).

Since the molecule has mainly alpha-helices, I am trying to use  Arcimboldo but 
with no luck.
I have used both the coiled-coil mode and normal mode for it and maximum value 
of CC after 5 cycles I get is closed to 20 that is not great for a solution. 
Even upon looking the structure solution by Arcimboldo, I found a lot of loops 
and I do not get any density for sidechains. A few of the parts of the helices 
and loops are overlapping.

I have used CCPi2 with the following options:
The assymmetric unit contains 1 molecule of mol wt 7300
search for 3 helices of length 14 residues

Any help will be appreciated.


Thank you
John


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-
Randy J. Read
Department of Haematology, University of Cambridge
Cambridge Institute for Medical Research Tel: +44 1223 336500
The Keith Peters Building   Fax: +44 1223 336827
Hills Road   E-mail: 
rj...@cam.ac.uk
Cambridge CB2 0XY, U.K.  
www-structmed.cimr.cam.ac.uk




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Re: [ccp4bb] Co crystalization with less soluble ligand.

[Frank von Delft]

And then of course, you need to decide whether you at all care to know 
anything about a compound that is so insoluble that it needs that kind 
of treatment  :)


On 23/06/2021 09:52, hoh wrote:

Hi

As total insolubility does not exist, I regularly use another method, 
which is to deposit a grain of the ligand directly into the drop.


In this case, we no longer control the concentration. The goal is to 
regularly freeze crystals (1 hour, 2 days, 1 week ..). Depending on 
the results, it is possible to adjust the time. If after one hour, the 
crystal no longer diffracts, redo the experience by freezing at 10s, 
30s, 2mn ..). If a blob appears, frozen after 1 week. This technique 
needs 2 things

, time and several exploitable crystals in the drop.


FH





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Re: [ccp4bb] Should Rmerge be reported?

[Frank von Delft]

Or just boycott the journal...??


On 10/06/2021 14:02, Tim Gruene wrote:

Hi Graeme,

could you explain why Rmeas does not serve the same purpose as Rmerge?
I guess Manfred (and others) have no objection to reporting Rmeas just
instead of Rmerge.

@ Christy: If one of my manuscript were rejected solely because Rmerge
was not mentioned, I would make a phone call to the boss if the editor.
Afterall, Rmerge can be recovered from the unmerged data, which ideally
you did deposit at the PDB.

Best,
Tim


On Thu, 10 Jun 2021 12:42:10 + "Winter, Graeme (DLSLtd,RAL,LSCI)"
 wrote:


Once again I find myself jumping to the defence of this rather poor
statistic!

Yes, Rmerge is a very poor estimator of "data quality" and has many
well published flaws related to multiplicity, but the low resolution
Rmerge, if combined with a multiplicity > (say) 5, is a good
indicator of whether the data set is "good" or there is something odd
going on.

For example, if you claim a 1.6A structure with an inner shell Rmerge
of 0.11, 5-fold multiplicity and an overall I/sig(I) of 68 I would
"smell a rat"

To me it does have a value, as an unbiased estimator of your true
unmerged I/sigma as it does not depend on any manipulation you have
done to your sigmas. It is not a good estimator of where the
resolution should be cut or any other decisions.

The above situation could be an indicator that there was radiation
damage, for example

There are better ways of measuring damage - Rd, Rcp, ... but these
are not commonplace graphs as I understand it. This little number in
the middle of the table does give you that hint.

So while I would say rejecting a paper because it was not included
was very heavy handed, I would not like to see it erased from all
papers either.

All the best Graeme

From: CCP4 bulletin board  on behalf of
Manfred S. Weiss  Sent: 10 June
2021 13:30 To: CCP4BB@JISCMAIL.AC.UK 
Subject: Re: [ccp4bb] Should Rmerge be reported?

Dear Cristy,

this is really hilarious. And it just shows how attached
some ppl are to outdated numbers. Against better
knowledge.

It has been shown many times that Rmerge is flawed
at various levels.

The only reason I can see to report it is to be backwards
compatible. But of course, this is a really weak reason.

I would love to see it disappear.

All the best
Manfred

Am 10.06.2021 um 14:25 schrieb Maria Cristina Nonato:
Dear Colleagues
Hope to find you all well and healthy.

I have a question regarding Rmerge. In recent years, we have
published our crystallographic structures in highly respected
journals using CC1/2, I/sigma(I), completeness and multiplicity as
quality parameters for our diffraction data.

Recently this year, We submitted a paper using the same strategy, but
one of the reviewers asked us to provide the Rmerge, arguing that
providing this data was compulsory and it was important to estimate
radiation damage.

We replied to the editor arguing that Rmerge should not be used as a
quality parameter, as suggested by more recent literature, such as
the article published by Karplus and Diederichs
(10.1016/j.sbi.2015.07.003). We also argued that there are modern and
efficient methods to estimate radiation damage (
doi.org/10.1107/S1600576718005241;
doi.org/10.1107/S0907444909040177).
It is my opinion that an experienced crystallographer can even
monitor radiation damage over the course of data processing.

And our paper was rejected  due to the fact I did not
provide Rmerge which I certainly could have done If I found necessary.

Journals like Nature ((https://www.nature.com › documents ›
nr-tables-xray)
and even IUCr Journals
(https://journals.iucr.org/f/services/structuralcommunications/)
still list Rmerge as a data to be reported. I always took this as a
suggestion since there are people still using Rmerge for data cutoff,
but I never took this as if Rmerge was a compulsory data to be
reported.

I would like to hear the opinion of this community. Should we
compulsorily report Rmerge?  If so, Why?

Cheers,

Cristy
--
Cristina Nonato
Associate Professor
Laboratório de Cristalografia de Proteínas
Faculdade de Ciências Farmacêuticas de Ribeirão Preto
University of São Paulo





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--
Dr. Manfred S. Weiss
Macromolecular Crystallography
Helmholtz-Zentrum Berlin
Albert-Einstein-Str. 15
D-12489 Berlin
Germany



Helmholtz-Zentrum Berlin für Materialien und Energie GmbH

Mitglied der Hermann von Helmholtz-Gemeinschaft Deutscher
Forschungszentren e.V.

Aufsichtsrat: Vorsitzender Dr. Volkmar Dietz, 

Re: [ccp4bb] writing coordinates of full biomol into one (PDB) file

[Frank von Delft]

Thanks for the quick responses!  I was looking for a command-line tool 
(should have said).  Here's the list:


1. phenix.pdb.biomt_reconstruction
2. Makemultimer.py: http://watcut.uwaterloo.ca/tools/makemultimer/docs 
<http://watcut.uwaterloo.ca/tools/makemultimer/docs>
3. Quat in pymol: https://pymolwiki.org/index.php/BiologicalUnit/Quat 
<https://pymolwiki.org/index.php/BiologicalUnit/Quat>
4. BiologicalUnit in pymol: 
https://pymolwiki.org/index.php/BiologicalUnit 
<https://pymolwiki.org/index.php/BiologicalUnit>


(CCP4bb is amazing)

Frank

On 25/05/2021 20:44, Frank von Delft wrote:

Hello all - this presumably has a really simple solution:

For a PDB file with a (correct) biomolecular assembly record (REMARK 
350), what program do I use to generate and write out the coordinates 
of the biomolecular assembly (or one of them).


Thanks
Frank



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Re: [ccp4bb] writing coordinates of full biomol into one (PDB) file

[Frank Von Delft]

Yes I thought so too, but discovered I am too stupid to decode the highly 
parsimonious manual on the ccp4 pages.

What I need is a command line that always works. Presumably that's a well 
defined problem...?



Sent from tiny silly touch screen<http://www.9folders.com/>

From: Debanu Das 
Sent: Tuesday, 25 May 2021 20:55
To: Frank Von Delft
Cc: CCP4BB@JISCMAIL.AC.UK
Subject: Re: [ccp4bb] writing coordinates of full biomol into one (PDB) file

Hi Frank,
PISA is your friend here.
Thanks,
Debanu

On Tue, May 25, 2021 at 12:44 PM Frank von Delft 
mailto:frank.vonde...@cmd.ox.ac.uk>> wrote:
Hello all - this presumably has a really simple solution:

For a PDB file with a (correct) biomolecular assembly record (REMARK
350), what program do I use to generate and write out the coordinates of
the biomolecular assembly (or one of them).

Thanks
Frank



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[ccp4bb] writing coordinates of full biomol into one (PDB) file

[Frank von Delft]

Hello all - this presumably has a really simple solution:

For a PDB file with a (correct) biomolecular assembly record (REMARK 
350), what program do I use to generate and write out the coordinates of 
the biomolecular assembly (or one of them).


Thanks
Frank



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Re: [ccp4bb] The weekly nonsense

[Frank Von Delft]

It's certainly a real problem they're writing about. Or at least, one that some 
people say we should be worrying about.

Sent from tiny silly touch screen

From: Jon Cooper <488a26d62010-dmarc-requ...@jiscmail.ac.uk>
Sent: Saturday, 23 January 2021 02:40
To: CCP4BB@JISCMAIL.AC.UK
Subject: Re: [ccp4bb] The weekly nonsense

Take care ;-

https://www.wicys.org/

Seems genuine enough group & everything to me. The referees should have spotted 
that one ;-0

Sent from ProtonMail mobile



 Original Message 
On 22 Jan 2021, 23:03, Bernhard Rupp < hofkristall...@gmail.com> wrote:

Dear CCP4 Fellows,

for the subscribers of my immensely popular show “The weekly nonsense” I 
recommend
https://arxiv.org/pdf/2101.06308.pdf
particularly reference [27] and its contextual environs.

Am I alone suspecting that this is some AI generated auto-paper-mill product?

Cheers, BR

--
Bernhard Rupp
The Amt
http://www.hofkristallamt.org/
b...@hofkristallamt.org
+1 925 209 7429
+43 676 571 0536
--
Many plausible ideas vanish
at the presence of thought
--




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Re: [ccp4bb] Open position - data management in biophysics

[Frank von Delft]

For me as hiring PI, what's repeatedly dismaying is that it's our 
funders and universities that set the terms, and only with extreme 
creativity can one shift the dial, and only on indidual recruitments, 
certainly not the high politics of the system as a whole.


No, I don't know what will break this - it exploits our fundamental 
weakness, that we go into science because we /want/ to do it, and are 
already investiging all our energy at convincing a system that something 
else is worth doing (getting our mad science funded at all) -- so things 
like collective striking or unionising don't really come naturally.


I do hope the next wave of scientists (am I that old already?) have some 
aggressively constructive thoughts, because mine and the one before mine 
sure don't.


Frank



On 20/01/2021 23:38, Navdeep Sidhu wrote:

Dear Gerlind, Markus, All:

Well, sometimes the (written) promise of a 2-year contract also ends up
boiling down systematically (for some PIs) to only a 6-month contract
after all.--And that after you've spent half a year or more and multiple
trips to the country concerned trying to get a work visa and housing,
all at your own expense--particularly tough for migrants and their families:

"Many come here with a promise of a two-year contract, which later turns
out to be a six month scholarship, which is renewed six months at a
time. Many feel that they have been fooled."
  - From Palle Liljebaeck. "Postdoctoral fellows at KI must be given
better terms." Naturvetarna (Sweden), Nov. 7, 2013
.

(By the way, work contracts often entail health, pension and other
benefits which may be limited or unavailable on a scholarship.)

Fortunately, many PIs don't agree with such practices. But they do
occur, including unfortunately for jobs advertized on the CCP4 bulletin
board--and so perhaps the IUCr or other institutions can help set better
standards.

Cheers,
Navdeep


---
On 20.01.21 22:34, Gerlind Sulzenbacher wrote:

Dear Markus,

thank you for opening this discussion.

I'd like to add that in some countries, like France, where I work, this
goes often along with with 12 months contracts.
Imagine moving continent, eventually with family (yes, PostDocs happen
to have a family) just for a 12 months contract, under the conditions
you mentioned.
Sad, as you said, ... and I am quite sure that it has not always been
like that.
I wish all members of the BB a good mood,
Best,
gerlind


On 20/01/2021 21:48, Markus Heckmann wrote:

Dear PI s, and senior scientists' involved in recruitment,

Why do so many (especially postdoc) positions these days indicate:


Readiness for high workload
able to work independently but also effectively and collaboratively
with other lab member
Candidates should have a documented publication record in
peer-reviewed journals, able to work both independently and as an
effective team member.

Do the candidates need to subtly understand that they need to work on
weekends or holidays? And what does it mean by independently and
collaboratively at the same time. Or is this a template from HR
departments.

Was it always like this in science world or we too need to work like
amazon warehouse workers (you can google it and see the pain)?

Saddened...

Mark
(not trying to point out any single PI/person but overall it is the
same words repeated...)




We are opening a new position for an upcoming European project.

*We are looking for an expert in scientific programming with
experience in
scientific data processing for a European project focused on
Standards for
Data Archival and Exploitation. *

Job description:

We offer attractive work connected to development of data management
infrastructure for biophysical data in the frame of an international
project at the Institute of Biotechnology in the centre of excellence
Biocev. The main responsibility lies in definition of data standards and
models for biophysical data, development of algorithms, design of user
interface, and realization of a pilot database of biophysical data. The
person is expected to actively participate in multilateral international
negotiations, to drive the tasks fulfillment in collaboration with the
local international partners, and to present the results.

Dear all,

Two postdoctoral positions are available in the laboratory of Dr.
Pengxiang
Huang, Assistant Professor and CPRIT scholar in cancer research in the
Department of Molecular and Cellular Biology at Baylor College of
Medicine.
With the long-standing interest in sterol lipids, the Huang lab
investigates
the poorly understood mechanisms involved in Hedgehog (Hh) and Wnt
signal
transduction, two related pathways that play critical roles in
development,
regeneration and cancer. We utilize a combination of biochemistry, cell,
chemical and structural biology approaches, including both X-ray
crystallography and Cryo-EM. Our recent 

Re: [ccp4bb] AlphaFold: more thinking and less pipetting (?)

[Frank von Delft]

I guess that also means that AlphaFold has learnt the 
crystal-structure-ness that older homology methods never achieved - 
which is why (anecdotally?) a "better" homology model tended to give 
worse MR performance than the "worse" template?


(Or something like that, I'm parrotting what I remember people (maybe 
Randy?) saying long ago about the problems with homology models in MR.)



On 04/12/2020 11:57, Adam Simpkin wrote:

I thought I might be able to add a little to this conversation as I performed 
some MR runs as part of the CASP14 High Accuracy analysis. There were 30 
targets with reflection data. Of these, AlphaFold2 models could be used to 
directly solve 24 structures after converting
RMS error predictions to simulated B-factors to aid the MR (10.1002/prot.25800).

Some of the models did contain sufficient local errors to impede MR. However, 
we were able to obtain a further 3 solutions by using AMPLE to truncate the 
models based on the per-residue RMS error predictions provided. In fact, a 
moderate truncation in AMPLE improved the quality of the MR solution in ~78% 
that succeeded by removing the few incorrectly models loops (typically at 
lattice interfaces).

A final thing to note was that the 3 structures that didn’t work still provided high 
quality model predictions (GDT_TS of 69, 84 & 83). These targets all contained 
multiple chains in the ASU and one was fairly low resolution (>3 Angstroms). 
Overall though I think the take home is clear, these models are really good and when 
the method or something similar is more publicly available I think it will definitely 
simplify MR for troublesome targets.

Best wishes,

Adam



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[ccp4bb] Help us help you: write support for Ultra-XChem beamline in Diamond-II

[Frank von Delft]

Dear all - please *help us help you*:

 * Some of you have used and even liked Diamond's XChem facility for
   crystal-based fragments screening.

 * Some of you have wanted to use it but didn't know how or didn't get
   time.

 * Lots and lots of you hope your crystallography will turn into
   chemical biology and drug discovery.

If you're one of those: *s*how your support for a lighting-fast XChem 
beamline in Diamond-II:


1. Dial in to the webinar next Monday 4pm (/details below/)
2. Sign up to the Interest Group (/here
   
<https://diamond.us20.list-manage.com/track/click?u=3de94671e0e91f373e1995d94=73866c46cb=b2cea28e06>//or
   linked below/)
3. Drop us statements of support (in this form
   
<https://forms.office.com/Pages/ResponsePage.aspx?id=dLonnQABDU2B_x1yja6N9sORn9fQKRxBrdwp3-jvXxFURTZRTU9VM1I2VVZEVEVFS1hJTlNHUThISi4u%C2%A0>
   or linked from here
   
<https://www.diamond.ac.uk/Home/About/Vision/Diamond-II/Flagship-Beamline-Projects.html#>)
4. Retweet this
   <https://twitter.com/FrankvonDelft/status/1326531394307158018>


Diamond-II is planning to upgrade and reinvent, by mid-2027; this 
includes new and upgraded beamlines - and rebuilding I04-1 as K04.  It 
should increase XChem throughput up to 15x, which means far bigger XChem 
fragment screens for far more of your projects, and (we conclude) far 
more of your chemical biology and drug discovery, much accelerated (e.g. 
this <https://www.biorxiv.org/content/10.1101/2020.10.29.339317v1?rss=1>).


We're about to submit the science case - and we're seeking as many 
statements of support as possible.


Please spread the word:  circulate to all your colleagues in chemistry 
and drug design and chemical biology - in fact, this touches so many 
discplines, you can probably send to just about everybody you work with...


Thank you for your help!
Frank


Prof Frank von Delft
Professor for Structural Chemical Biology
Principal Beamline Scientist: I04-1/XChem
Diamond Light Source

Principal Investigator: Protein Crystallography
Centre for Medicines Discovery
Oxford University





 Forwarded Message 
Subject:Diamond-II Webinar: K04 Beamline Rebuild for Ultra-XChem
Date:   Mon, 9 Nov 2020 09:54:39 +
From:   Diamond Communications 
Reply-To:   Diamond Communications 
To: frank.von-de...@diamond.ac.uk




 Diamond-II Webinar: K04 Beamline Rebuild for Ultra-XChem

*Monday 16th November 2020, 16:00-17:00
Click here to visit the event page 
<https://diamond.us20.list-manage.com/track/click?u=3de94671e0e91f373e1995d94=1134639c78=b2cea28e06>*


Dear Colleagues,

Structural and chemical biologists and medicinal chemists are warmly 
invited to this webinar, which will describe the rebuilding of beamline 
I04-1 as K04 for Diamond-II. The project will achieve ultra-high 
throughput XChem fragment screening and thereby help drive routine and 
rapid pre-clinical impact in structure-based drug discovery and chemical 
biology. Diamond-II 
<https://diamond.us20.list-manage.com/track/click?u=3de94671e0e91f373e1995d94=99d1909760=b2cea28e06>is 
a coordinated programme of development that includes a major upgrade of 
the storage ring to deliver low emittance at higher energy, along with a 
range of rebuilt and enhanced beamlines. The K04/XChem project is part 
of a transformational change for the MX and XChem communities, and 
attendance and feedback are highly encouraged.


*Proposal background*
The K04/XChem flagship builds on the success and oversubscription of the 
XChem fragment screening facility 
<https://diamond.us20.list-manage.com/track/click?u=3de94671e0e91f373e1995d94=2204b7381d=b2cea28e06>, 
developed in tandem with the evolution of beamline I04-1. The facility 
provides a world-unique offering for structure-based drug design, and is 
in heavy academic and industrial demand, with the resilience to support 
significant COVID 
<https://diamond.us20.list-manage.com/track/click?u=3de94671e0e91f373e1995d94=de1fafe6c2=b2cea28e06>work 
<https://diamond.us20.list-manage.com/track/click?u=3de94671e0e91f373e1995d94=28fc8c1744=b2cea28e06> during 
lockdown.


The Diamond-II machine configuration necessitates removing beamline 
I04-1, providing the opportunity to rebuild it on the new K04 straight, 
delivering a beamline of vastly increased flux and brilliance, along 
with extreme automation. The resulting order-of-magnitude increase in 
throughput will fundamentally shift the scientific scope of 
crystallographic fragment screening. On the one hand, a far larger range 
of classes of drug targets will become viable, even when diffraction is 
weak. On the other hand, routinely large experiments will help achieve 
the coming revolution in rational drug discovery, by allowing all key 
interactions and conformations to be observed in 3D up front, providing 
the raw data that future algorithms will be able to exploit to design 
clinic-ready drug candidates from scratch


*User 

Re: [ccp4bb] [EXTERNAL] Re: [ccp4bb] AW: Going back to Coot 0.8

[Frank von Delft]

I believe Paul is trying to make the caffeine materialise directly in 
your bloodstreams.


He seems to have forgotten that people actually like harvesting and 
roasing the coffee beans and folding the paper cup - so even if he 
figured out how to simulate the burning sensation in your throat as the 
hot coffee goes down, it would still frustrate a significant section of 
people.


I suspect in the long term, we'll get comfortable with just the caffeine 
hit.






On 09/09/2020 21:27, Schulz, Eike-Christian wrote:

Hi Tim,

I don't think that metaphor is quite correct. To me it seems that no matter 
what button you pushed you got coffee. In my opinion intuitive software is a 
blessing and should not easily be disregarded.

But as I said before, I am happy to read into new stuff.

Also there seem to be mixed experiences here. Might this be map-resolution 
related ?

Best,

Eike



-Original Message-
From: CCP4 bulletin board  on behalf of Georg Zocher 

Reply to: Georg Zocher 
Date: Wednesday, 9. September 2020 at 22:17
To: "CCP4BB@JISCMAIL.AC.UK" 
Subject: Re: [ccp4bb] [EXTERNAL] Re: [ccp4bb] AW: Going back to Coot 0.8

 Dear Herman,

 Am 09.09.2020 um 17:46 schrieb Schreuder, Herman /DE:
 > The old real-space refinement was intuitive and easy to use and did 
exactly what the user expected, without having to consult the manual! The result 
might not have been perfect, but was good enough for subsequent Refmac, Buster, 
Phenix refinement.

 That fits perfectly to my user experience with RSR in coot 0.8.x. and
 also explains why at least a number of people having some issues with
 the new RSR.

 All the best,

 Georg

 

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Re: [ccp4bb] metal coordination at low resolution - restraints

[Frank von Delft]

Surely an opportunity for machine learning to make a real difference?  
There's enough data in the PDB by now, that you can conceive of a 
classifier generating the most likely set of restraints appropriate 
given an OMIT map.




On 09/09/2020 11:37, Eleanor Dodson wrote:
I know how difficult it is to get the chemistry right, and that really 
has to be up to the researcher..
 a database of high resolution structures with metals would be useful 
as a sanity check. Robbie mentioned

 MetalPDB (http://metalweb.cerm.unifi.it/).

E

On Wed, 9 Sep 2020 at 11:18, Garib Murshudov > wrote:


Hi Eleanor,

Obviously I agree that people should use restraints for metals. It
will make metal refinement easy and coordination consistent with
chemistry

For distance and angle restraints there is an external distance
restraint mechanism. PDB-REDO can generate for some of the metals.
Unfortunately it is not easy in general. But can be done manually.

If you know metal and coordinating atoms and coordination then
putting restraints manually in ccp4i2 refmac keyword part should
be straightforward. For example (I think it is correct)

External distance first chain A residue 239 atom ZN second chain A
residue 500 atom O value 1.95 sigma 0.032 type 0
External distance first chain A residue 239 atom ZN second chain A
residue 145 atom ND1 value 2.03 sigma 0.05 type 0
External angle first chain A residue 500 atom O next chain A
residue 239 atom ZN next chain residue 145 atom ND1 value 109
sigma 5 type 0


Unfortunately these restraints do not account for the fact that
when Zn is bound to O or N atoms then it may change the nature of
bonds (i.e. ZN bonds are often covalent like, as Robbie says:
these are d-block atoms for you)
The values above assume that ZN coordination is 4 and it is
tetrahedral. For others similar restraints could be added.

In future we would like to semi-automate metal refinement. At the
moment it is pretty much users’ responsibility to design correct
restraints (it is not ideal, not because we do not trust users but
because the knowledge is not easily transferable from one
refinement to another).


Regards
Garib





On 8 Sep 2020, at 20:51, Eleanor Dodson
mailto:eleanor.dod...@york.ac.uk>> wrote:

Yes Garib - all true but I dont think people should try to impose
restraints initially in refinement of metals.

I never (knowingly)  keep the metals in my MR model. Searching
for them with phases from a putative MR solution is one of the
best verifications that it is right...

You can use anomalous fouriers to fix the metals as accurately as
possible. That could help with issue 3. And peak heights give you
a bit of information re occupancy.

Surely issue 2) shouldnt happen!  Do you mean BUCCANEER builds
the sequence wrongly?

Na etc.. Impossible - hate them..

4) & 5) are more or less the same .. occupancy is tricky - again
anom peaks ? Occupancy refinement? all difficult at low resolution..

On Tue, 8 Sep 2020 at 20:29, Garib Murshudov
mailto:ga...@mrc-lmb.cam.ac.uk>> wrote:

Hi Jan,


It is my experience also that if atoms are in more or less
correct positions then non-bonding interaction together keep
metals in correct positions, perhaps with a little bit
different metal-coordinating atom distances.
Problems arise when 1) one or several of the corrdinating
atoms are missing which is the case at low resolution. Light
atoms are almost invisible around heavy atoms (series
termination and B value effects); 2) there are conflicting
restraints which often happens with SS-bond (wrong SS-bond)
and Zn-Cys bonds; 3) Starting atomic coordinates are far from
right positions (which happens after molecular replacement
when conformations are not exactly same around metals; 4)
Metals are not fully occupied (which happens when metals
involve reaction and they arrive during or as a part of
reaction); 5) non-specific metal binding sites (which happens
when metals are not part of the molecule but are used as a
part of sample preparation - crystallisation or otherwise).
6) light metals (Na and similar) when metals are difficult to
distinguish from water molecules; 7) highly mobile metals.


Regards
Garib



On 8 Sep 2020, at 13:01, Jan Dohnalek mailto:dohnalek...@gmail.com>> wrote:

Hi Garib,




On 8 Sep 2020, at 11:39, Jan Dohnalek
mailto:dohnalek...@gmail.com>>
wrote:

These are structural.


Are they tetrahedral or octahedral? From the list of
neighbours they do not look like tetrahedral. Some of
them do look like octahedral.

They 

Re: [ccp4bb] RES: [ccp4bb] Macromolecular Crystallography workshop in South America 2020

[Frank von Delft]

Thanks Stephen for reminding me there's a point no-one raised at the time:

There are two sets of people that have agency in this:  1) the 
organisers, and 2) the ones that get the invites.


Group 1 already have a tough job:  organising a meeting is a pile of 
work - so go easy on them.  (Or organise one yourself, and have fun.)



It's Group 2 that is by far the largest and most powerful:  we who are 
in it really do not need to accept /every/ /single /invitation; it is 
not only in our power but also our duty (on many levels) to send group 
members or collaborators instead - even just occasionally can already 
make a difference.


And then suddenly we discover all these female and minority and other 
under-priviledged speakers that lie in our gift to advance - and even 
better, we get to do some mentoring while we're at it, not least to 
teach that most insidious skill that we the priviledged were handed for 
free, namely how to wear our priviledge lightly by taking it for granted.


(I cannot of course claim this insight as my own, or even claim to be 
particularly consistent at it - so I must thank group members and 
colleagues and spouses for making the penny eventually drop by holding 
my toes to the fire.)



But yes, organisers:  you /can/ ask your invitees to help you, by 
reminding them that you're not in fact interested /in //them as 
speakers, /just in having their work presented at your meeting -- so 
could they please suggest someone suitable.


phx.













On 23/07/2020 10:21, Stephen Curry wrote:

It has been on my mind to respond to this thread since I was made aware of it 
in late February. Not because I regard myself as any sort of sage on these 
matters, but because I received a phone call from someone asking me to speak 
out. This person did not want to give her name and or to go into specific 
details, but it was clear that the issue matters a great deal to her. 
Unfortunately, she called while I was in the midst of trying to do three other 
things, so I did not give our discussion all the attention it deserved and that 
is a matter of some regret. I hope I can make some small amends by contributing 
here.
First off, I make no pretence at expertise. And nor am I going to pick up on 
individual comments, I just want to make some general observations and 
suggestions.

It is good to see this discussion happening within the CCP4 community and to 
see so many people engage. The question of female representation in academic 
workshops and conferences is a live one and one where we as a community must do 
better. This is not simply a matter of suggesting that more women should step 
forward to volunteer their services. And nor would I suggest having women-only 
events, except perhaps as a provocative experiment to give those of us in the 
majority (i.e. white men) a little taste of what it feels like to be excluded.

To my mind the key here is to recognise the systemic biases and accept that we 
all have a responsibility to fix the system. We can’t simply leave ‘solving the 
problem’ to those in the under-represented groups (whether they be women, 
people of colour, disabled people etc). It is tiring for women (and other 
minoritized groups) to keep having to point out what is wrong;  that burden in 
itself is part of the structural bias. And nor should we ignore or silence 
their concerns because we have not seen or experienced them ourselves.

Listening has to be a central part of the process, or ‘people talking to 
people’ as Atul Gawande puts it in an insightful piece about how to get people 
to see things from a different perspective 
(https://www.newyorker.com/magazine/2013/07/29/slow-ideas). This isn’t always 
going to be easy, but if we are really committed to including all people of 
talent within the scientific community and enjoy the intellectual fruits (and 
justice…) of diversity, we need to be prepared for what Margaret Heffernan 
(another of my favourites) might call ‘creative conflict’ 
(https://www.ted.com/talks/margaret_heffernan_dare_to_disagree?language=en).

Of course, tools and processes will also help. I agree with those who suggest 
that we should be proactive about seeking out women and other under-represented 
folks when looking for workshop tutors or conference speakers (or new people to 
hire). To that end, at Imperial we have introduce a new conference policy 
(which others are free to copy – that is in part how we constructed it 
ourselves - 
https://www.imperial.ac.uk/equality/governance/policies/conference-policy/). 
This sets out not only a code of conduct but also guidance on how to ensure 
better representation among speakers and panellists at workshops and 
conferences. Those of us in the majority who are accustomed to receiving 
invitations to speak have a crucial role to play here in testing the 
organisers’ commitment to diversity. I have a personal policy of not appearing 
on all-male panels or line-ups of speakers. I am now also trying to 

Re: [ccp4bb] [EXTERNAL] Re: [ccp4bb] number of frames to get a full dataset?

[Frank von Delft]

Gerard, fantastic proposal - let's call it "abundancy"!!!

Which developer will be the first to change their logfile?


On 30/06/2020 16:38, Gerard Bricogne wrote:

Dear Phil,

  I would like to make an attempt to not let this question get mired in
exchanges of well-researched linguistic arguments at risk of being drowned
in a cacophony of sound bites :-) .

  You refer to the days of SCALA, at which time data were collected on
CCD detectors, whose lengthy read-out times led to designing data collection
strategies so that they would achieve completeness in the smallest number of
"frames", themselves chosen as thick-sliced as possible while avoiding
angular overlap because of the read-out noise added to each such frame. With
this mindset, measuring again a reflection that had already been measured
could have been viewed as a waste of effort, bringing water to the mill of
interpreting "redundancy" as a sign of sub-optimality. However, looking
again at the CCD datasets collected according to this paradigm, they are
dire! Minimal availability of symmetry-related measurements made internal
scaling fragile, the terrible corner effects in the 3x3 detectors could not
be corrected, and the tracking of radiation damage was beyond hope.

  A lot has happened since, namely pixel-array detectors, fine-sliced
images recorded at low transmission, aiming at recording symmetry-related
reflections "a large number of times" - whatever one ends up calling that.
Far from being superfluous, or "redundant" in the negative sense of the
term, these "abundant" measurements (to coin a phrase) are now recognised as
being absolutely crucial towards the rejection of outliers, a key process in
obtaining high-quality data. This would then bring us back to the positive,
even noble connotation of the term "redundancy", since an abundance of
symmetry-related measurements now allows the detection and rejection of the
dodgy ones. From that perspective, "redundant" is good in the sense Ian
mentioned in relation to aviation equipment: if a few of those measurements
are rotten, you can throw them away and still have some left to do the job.
If you have abundant measurements and just call them multiple, this sense of
allowing rescue in case of failure disappears, and with it an important
aspect of why one should go for strategies that harvest symmetry-related
measurement in high numbers. This is why I ceased to support the standard
term "multiplicity" in conversations with Ian and went along with his choice
of the term "redundancy" in the presentation of STARANISO results.


  With best wishes,

   Gerard.

--
On Tue, Jun 30, 2020 at 02:30:27PM +0100, Phil Evans wrote:

I changed the annotation from “Redundancy” to “Multiplicity” in Scala, later in 
Aimless, after I was taken to task by Elspeth Garman with the argument as 
stated, that if it’s redundant why did you bother to measure it?

(this one could run and run …)

Phil


On 30 Jun 2020, at 14:07, Ian Tickle  wrote:


I agree about RAID but I would go a lot further.  There seems to be some confusion here over the correct meaning of 
'redundant' as used in a scientific context.  I don't think looking it up in an English dictionary is very helpful.  So 
as has been mentioned the non-scientific and rather imprecise meanings are "not or no longer needed or useful; 
superfluous" or "exceeding what is necessary or natural; superfluous" and "needlessly repetitive; 
verbose".  In fact both redundant and abundant have the same Latin etymology, and redundant literally means 're' 
(again) + 'unda' (wave), i.e. 'repeating as a wave'.  The original meaning in English is in fact 'over-abundant' and is 
still used in poetry with that meaning (e.g. "as redundant as the poppies in the field").  There's of course 
also the meaning 'dismissal from a job due to a need to reduce the head count' and from there 'out of work', but that's 
relatively recent having been coined by a UK Government official in the 1900s!

The correct and totally precise scientific meaning which is appropriate in the 
context of this discussion is to be found here: 
https://en.wikipedia.org/wiki/Redundancy_(engineering) .  Note that it applies 
equally to both hardware and software engineering:

Redundancy is the duplication of critical components or functions of a system 
with the intention of increasing reliability of the system, usually in the form 
of a backup or fail-safe, or to improve actual system performance.

Nothing there about not or no longer needed or useful, superfluous, needlessly 
repetitive, verbose!  Note that 'multiplicity' totally fails to carry the 
connotation of increasing the system reliability by duplication (i.e. there are 
multiple copies but there's nothing that indicates the justification for them). 
 Redundancy occurs in TMR (triple modular redundancy) systems used (as I guess 
Bernhard knows well) in triplicated control systems in commercial aircraft.  I 
don't know about you but I 

Re: [ccp4bb] 2fofc maps from refmac twinned refinement - clarify?

[Frank von Delft]

Thanks all - also for jogging my memory.

Peter, I think Garib ended up doing something statistically 
sophisticated, but I couldn't track down the slides or documentation I 
remember seeing somewhere.  But I didn't dig very hard, and if it's been 
there since 2012, then that explains why I failed.


Thank god your supervisor and his/her ilk haven't had sole discretion 
over the research funding that's been supporting the algorithm and 
method developers all these decades;  if they had, we'd still in the 
year 2020 be wasting millions per project just to get those 200um 
crystals that yield the signal needed for the ancient algorithms to 
recognise the presence of a diffraction spot.


The other quiet revolution in structural biology:  algorithms.

Frank



On 29/04/2020 21:53, Petrus Zwart wrote:
I am not quite sure how it is done in Refmac, but in phenix it works 
as follows


- difference maps are gradient maps for a least squares target and 
they do not contain any amplitude contamination from twinning.


- Fo type maps are computed either via classic detwinning (solving the 
linear equations) or this is done using some proportionality rule like 
James and Eleanor allude to.


An alternative way would be use something like this relation

Map coefficients we want: 2Fo-Fc

Realize that 2Fo - Fc = Fc + 2(Fo-Fc)

and compute

Fcalc + 2*difference map*magic scale factor

It is a bit of a hack, no FOM's etc and I worry about bias. It would 
be far better to get map coefficients from the joint distribution of 
the structure factors that take into account twinning. In this way, 
you can handle experimental error as well in a proper fashion. I 
wouldn't be surprised if this happens in Refmac, it doesn't in Phenix 
(yet).


My PhD supervisor's advice always holds btw: "Grow better crystals"

Regards
Peter





On Wed, Apr 29, 2020 at 12:40 PM James Holton <mailto:jmhol...@lbl.gov>> wrote:


Yes, they are "de-twinned".  There is really no other way to do it.
Without de-twinning you'd be looking at a map of two overlapping
structures.  How do you turn a single observation of the sum of
intensities from two different hkls into two different Iobs
values? You
need to know the ratio.  The twin fraction is one way, but once it
gets
close to 0.5 the "de-twinning" gets very noisy.  I believe what the
refinement programs do is use the ratio of the two Fcalc^2 values in
order to "split" the Iobs value. Doesn't that introduce "bias"? 
Yes, of
course it does.  That's one of the many reasons why twinning sucks.

Now, of course, there are probably fancy weighting schemes that make
things a bit better, but rather than speculate I'd ask the program
authors themselves.  The best thing, of course, is to refine until
Icalc
becomes more accurate than Iobs, which is the typical result of
small-molecule refinements.  I expect that is why they are not
nearly as
afraid of twinning as we are.

-James Holton
    MAD Scientist


On 4/28/2020 2:19 PM, Frank von Delft wrote:
> Hi all - feel free to point me to the docs if it's already clear
> somewhere:
>
> When refmac generates 2mFo-DFc maps after twinned refinement,
are they
> the "untwinned" view of the electron density?  I.e. with the
twinnig
> convoluted out by his statistical magic?
>
> I remember Garib mentioning the ambition a few years ago;  but I've
> not been paying enough attention to remember if it's actually
> implemented, or still in progress (because it's hard).
>
>
> Thanks
> Frank
>
>

>
> 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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--

P.H. Zwart
Staff Scientist
Molecular Biophysics and Integrated Bioimaging &
Center for Advanced Mathematics for Energy Research Applications
Lawrence Berkeley National Laboratories
1 Cyclotron Road, Berkeley, CA-94703, USA
Cell: 510 289 9246

PHENIX: http://www.phenix-online.org <http://www.phenix-online.org/>
CAMERA: http://camera.lbl.gov/
-



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Re: [ccp4bb] disinfecting keyboards

[Frank Von Delft]

Make your users wear masks.

Sent from tiny silly touch screen

From: David Schuller 
Sent: Wednesday, 29 April 2020 21:03
To: CCP4BB@JISCMAIL.AC.UK
Subject: Re: [ccp4bb] disinfecting keyboards

If you are going that route, it would make sense to locate the UV lamps in the 
X-ray hutch, since those already have safety interlocks, etc. The X-ray beam 
itself is too directional to uniformly cover much.


On 2020-04-29 15:48, Eduardo Rodríguez-Román wrote:
Hi Tim,
It may be convenient to install a UV light lamp in the room. Have you thought 
about that?
I do not know if any of the equipment may suffer damage in the medium or long 
term due to the incidence of UV light. You must evaluate this.
UV light is used in different microbiology laboratories around the world to 
sterilize the work area.
Just turn on the UV light about ten min before entering the room, then turn off 
the UV light, and wait another 15 min to enter. When leaving, turn on the UV 
light for 10 min, and then turn off.
The UV light on/off switch should be located outside the room.
Best,
Eduardo.

On Wed, Apr 29, 2020 at 2:53 PM Tim Gruene 
mailto:tim.gru...@univie.ac.at>> wrote:
Dear all,

can you make suggestions for how to disinfect computer keyboards, and
instrument panels?

Our facility is going to reboot next week, with shifts so that people
don't meet. The main interface will be the computer keyboards, as well
as the door of our X-ray diffractometer and the mounting of the
crystals.

The keyboard labels may not like alcohols (and the efficiency of
injecting disinfecting through the USB cable is also under discussion,
so I heard).

One way would be to use individual keyboards, and wearing gloves for
replugging, and to use gloves for mounting crystals.

But maybe there are other ways that won't require gloves?

Best regards,
Tim

--
--
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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--
Eduardo Rodríguez-Román, PhD
ASM, eLIFE & USERN Ambassador
Biotechnology and Plant Virology Lab
Center for Microbiology and Cell Biology
Instituto Venezolano de Investigaciones Científicas
PO Box 20632, Caracas 1020A, Venezuela.
ORCiD: orcid.org/-0001-8717-7527
Phone: +58 (212) 504 1189/1366/1500
Cell phone: +58 (424) 111 0375
E-mail: ejrodrig...@ivic.gob.ve,
or erodriguezro...@gmail.com
Twitter: @erodriguezroman
 
[https://docs.google.com/uc?export=download=1_MmmlkLEEx67-CUSQYLGHM9eAuWKgHX0=0B7ogjC4ootvrUi9ITGpVWEd4S01rVnBVTjVvd3p0OUN5d1hRPQ]
   
[https://drive.google.com/uc?id=1rHts30EjUWzlunzrJxVquEu_aYsfYmHE=download]
 
[https://docs.google.com/uc?export=download=1eQDqlB4kvjK2qLYX3htqhh54b-l76rcs=0B7ogjC4ootvrNy9vbGtQb0h4YkhUK2J5MmZvczhMK0NBbks0PQ]
 
[https://docs.google.com/uc?export=download=1CekoNvw6Til3qV0zBn5Vohz05SD-nyTR=0B7ogjC4ootvrRFhPTzJiMFBrZ1ZqRUpJYTRDZ0FBRDFkT28wPQ]




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--
===
All Things Serve the Beam
===
   David J. Schuller
   modern man in a post-modern world
   MacCHESS, Cornell University
   schul...@cornell.edu



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[ccp4bb] 2fofc maps from refmac twinned refinement - clarify?

[Frank von Delft]

Hi all - feel free to point me to the docs if it's already clear somewhere:

When refmac generates 2mFo-DFc maps after twinned refinement, are they 
the "untwinned" view of the electron density?  I.e. with the twinnig 
convoluted out by his statistical magic?


I remember Garib mentioning the ambition a few years ago;  but I've not 
been paying enough attention to remember if it's actually implemented, 
or still in progress (because it's hard).



Thanks
Frank



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Re: [ccp4bb] AW: [EXTERNAL] Re: [ccp4bb] on-topic: your opinions requested!

[Frank von Delft]

I meant:  complain to the editor for accepting a paper without released 
coordinates.  We as a community fought and won that battle >20 years ago 
- so we have the weight of history on our side.



On 07/04/2020 17:05, Schreuder, Herman /DE wrote:


Dear Frank,

here I disagree. I think it is bad practice to complain to the editors 
or start naming and shaming before asking the authors first. Only if 
they do not want to cooperate, it would be time to bring the 
flame-throwers in position.


However, I think the situation is more subtle and that that is the 
reason Artem wrote his email: He wants the data, but does not want to 
reveal his identity to his competitors, who apparently made a 
significant effort not to reveal any useful details.


Here I would let me guide by the (perceived) commercial interest: if 
it is not gigantic, then I would contact the authors to prevent a 
wasteful duplication of research efforts.


If there is a significant commercial interest, it would probably be 
better not to contact them and go the hard way of solving the 
structure yourself. A thing to consider is also what would happen if 
the authors still would refuse: they know the identity of the 
competitor and you still do not have the data.


An alternative may be to ask an academic friend who also works on 
sausage esterases to inquire with the authors…


Good luck with your decision!

Herman

*Von:* CCP4 bulletin board  *Im Auftrag von 
*Frank von Delft

*Gesendet:* Dienstag, 7. April 2020 17:19
*An:* CCP4BB@JISCMAIL.AC.UK
*Betreff:* [EXTERNAL] Re: [ccp4bb] on-topic: your opinions requested!

*EXTERNAL : *Real sender is owner-ccp...@jiscmail.ac.uk 
<mailto:owner-ccp...@jiscmail.ac.uk>


Write to the editor - that's their job.

Though they may also see it as their job to ignore emails like yours 
because that's far easier than dealing with them.


Alternatively, go the Rupp Route:  Name and Shame! ;)

On 07/04/2020 16:08, Artem Evdokimov wrote:

Dear CCP4ers,

I would like to solicit your thoughts on the following (this is a
real situation, but salient details are changed):

Imagine that you're an industrial scientist in a small company,
working on the Bavarian Sausage (Weisswurst) Esterase project. The
overall structure is previously unknown, with no good homologs in
the PDB, trying to model is "OK not great" so the structure is
really needed...

Then, you find an article from a large commercial competitor, that
somehow managed to solve the Stadtwurst (Saxony Sausage) Esterase
structure (which is a very close homolog to the one you need!).

Sounds good - but as you read the paper you realize that the
authors managed to find a journal that allowed them to publish
their work without disclosing neither the coordinates of the
model, nor even the crystallization conditions of the protein -
all that's available is a tantalizing still picture of the active
site in surface mode, with a ball-and-stick ligand positioned such
that it is impossible to say what it interacts with.

So you sit and ponder - whether to write to the Editor, or maybe
to contact the authors directly (but then they would know that
you're working on this, which is not necessarily great since
you're competing), or to just buck up and do the structure on your
own (which feels a bit wasteful). Then, you realize that your
friends at CCP4 have a lot of wisdom to offer, so you sit down and
pen an email...

Any thoughts?

Artem



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Re: [ccp4bb] on-topic: your opinions requested!

[Frank von Delft]

Write to the editor - that's their job.

Though they may also see it as their job to ignore emails like yours 
because that's far easier than dealing with them.


Alternatively, go the Rupp Route:  Name and Shame! ;)


On 07/04/2020 16:08, Artem Evdokimov wrote:

Dear CCP4ers,

I would like to solicit your thoughts on the following (this is a real 
situation, but salient details are changed):


Imagine that you're an industrial scientist in a small company, 
working on the Bavarian Sausage (Weisswurst) Esterase project. The 
overall structure is previously unknown, with no good homologs in the 
PDB, trying to model is "OK not great" so the structure is really 
needed...


Then, you find an article from a large commercial competitor, that 
somehow managed to solve the Stadtwurst (Saxony Sausage) Esterase 
structure (which is a very close homolog to the one you need!).


Sounds good - but as you read the paper you realize that the authors 
managed to find a journal that allowed them to publish their work 
without disclosing neither the coordinates of the model, nor even the 
crystallization conditions of the protein - all that's available is a 
tantalizing still picture of the active site in surface mode, with a 
ball-and-stick ligand positioned such that it is impossible to say 
what it interacts with.


So you sit and ponder - whether to write to the Editor, or maybe to 
contact the authors directly (but then they would know that you're 
working on this, which is not necessarily great since you're 
competing), or to just buck up and do the structure on your own (which 
feels a bit wasteful). Then, you realize that your friends at CCP4 
have a lot of wisdom to offer, so you sit down and pen an email...


Any thoughts?

Artem



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Re: [ccp4bb] COVID-19 protease inhibitors - 2nd call for designs - Thurs midnight

[Frank von Delft]

Hi Nick - it is we that thank you all; and apologies for the tight 
deadlines, all I can say is we'd be a bit more thoughtful but CoV-2 is 
not being particularly obliging either...


There will be at least one more round, deadline approximately one week 
later;  and we may have additional fragments because Diamond came back 
up this week, just for COVID work.


Speaking of which:  reminder that if you need a synchrotron or cryoEM 
for COVID work, you can put in rapid access proposals - details on 
Diamond's website.


(I'll stop spamming the list now - thanks for your forebearance.)

Frank



On 02/04/2020 01:01, Nicholas Larsen wrote:
Hi Frank, I thought we were working quickly, but we only just got all 
of your structures uploaded in our Proasis system today and can only 
now begin analysis and design ideas. I don't know if we will have much 
of anything by your deadline. Will there be additional design rounds?  
Thanks again for making all this data available and it really is 
inspirational what your team is doing to confront collaboratively this 
global crisis.

Best,
Nick

On Wed, Apr 1, 2020 at 10:16 AM Frank von Delft 
mailto:frank.vonde...@sgc.ox.ac.uk>> wrote:


All - last week's call for compound designs to the CoV-2 main
protease (https://covid.postera.ai/covid)
elicited an astonishing response...  (I confess I was quite taken
aback.)

I just realised I should let this BB know the second call for
designs is now open. *Deadline is tomorrow 23:59 PST (April 2nd).
*(Apologies for those that weren't following on twitter.)*

*Two things:

  * we're asking for designs especially focusing on covalent
inhibitors (read more here

<https://discuss.postera.ai/t/screening-cascade-fast-track-and-regular-track-of-designs/567>)
  * the most convincing designs will be fast-tracked by spending
more money to cut several weeks off the testing (read more
here

<https://discuss.postera.ai/t/screening-cascade-fast-track-and-regular-track-of-designs/567>)

Happy designing!

Frank



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[ccp4bb] COVID-19 protease inhibitors - 2nd call for designs - Thurs midnight

[Frank von Delft]

All - last week's call for compound designs to the CoV-2 main protease 
(https://covid.postera.ai/covid)

elicited an astonishing response...  (I confess I was quite taken aback.)

I just realised I should let this BB know the second call for designs is 
now open. *Deadline is tomorrow 23:59 PST (April 2nd). *(Apologies for 
those that weren't following on twitter.)*


*Two things:

 * we're asking for designs especially focusing on covalent inhibitors
   (read more here
   
)
 * the most convincing designs will be fast-tracked by spending more
   money to cut several weeks off the testing (read more here
   
)

Happy designing!

Frank



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Re: [ccp4bb] Paired refinement proves data quality goes beyond the spatial limits of the detector

[Frank von Delft]

That is awesome.  It means we can add data up to a kilometer out, and 
start modelling quarks?


I urge the community to deposit all raw data to a virtual detector of 
1km in size - I'm sure Google will happily stump up for the storage 
costs, the business case is unarguable.





On 01/04/2020 05:36, Petr Kolenko wrote:

Dear colleagues,
We, the developers of a program for paired refinement, have found a remarkable 
feature that should be shared with the community. The fact that data beyond the 
arbitrary cutoff may cause an improvement of electron density and make your 
models better is generally accepted. We found now that the data beyond the 
dimensions of the detector are still useful, should be used in refinement, 
deposited in your structure factor file and if possible, made publicly 
available in data repositories as well! This leads us to a general 
recommendation, please deposit your raw data including regions beyond the 
detector edge or better the corner.  Share the maximum available and be FAIR.
Stay safe, best regards,
Petr



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[ccp4bb] COVID-19 - help design protease inhibitors - 1st round Thurs midnight

[Frank Von Delft]

To all you structural biologists locked out of your labs, bored with answering 
emails or writing your non-COVID paper, and itching all your lives to be 
medicinal chemists, here's your chance:

https://covid.postera.ai/covid

And you get to do something directly on COVID too.

It's easy:

  *   stare at the pile of fragments we found bound to the SARS-CoV-2 Main 
Protease in our somewhat epic XChem fragment 
screen<https://www.diamond.ac.uk/covid-19/for-scientists/Main-protease-structure-and-XChem.html>
 this month (alluded to by others)
  *   see if you can spot cool ways of (especially) merging those hits - or 
anything else
  *   draw the compound onto that page
  *   hit submit

It's actually a bit harder than it sounds - so we're betting that many brains 
will crack the nut of hitting potency in one go (!).

We will do the rest - well, we'll try, if the Filters Approve and the Funds 
Permit -- and even for that, you can contribute, or tell people that could 
contribute (details on that page).

First collection closes tomorrow (Thurs) midnight Pacific Time (but there will 
be more).


Yes, it is a huge social experiment and a total crapshoot - but we must do 
something!  So thank you for all and any help...

*** Do forward to anybody relevant, especially experienced medicinal chemists.

*** If you know virology labs set up to do SARS-CoV-2 assays, email the address 
on that page.

*** If you have help to offer or wisdom to share, do so on the forums on that 
page

*** If you want to use the data for anything else - PLEASE DO - we were anxious 
to push it out ahead of PDB release cycle or getting preprint written.


Frank


--
Prof Frank von Delft
Professor for Structural Chemical Biology

Principal Beamline Scientist: I04-1 and XChem
Diamond Light Source
+44 1235 778997 (office: M,T,T)
+44 7471 026103 (mobile)

Principal Investigator: Protein Crystallography
Structural Genomics Consortium
Oxford University
+44 1865 617583 (office: W,F)





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Re: [ccp4bb] [3dem] Which resolution?

[Frank Von Delft]

Belatedly, but since the thread is still alive:  Thank you Colin for answering 
my request - super informative, as were the later posts on B-factor and 
sharpening.

It all reinforces my prejudice:  we need to turn to interpretability, i.e. the 
next step (modelling), to inform the question of information content.  There 
can surely be no other way, and it will require automated modelling.  Which 
sucks if you're a microscopist waving your hands at blobs of colour to get 
manuscript into Nature.  Or for that matter a crystallographer, waving your 
hands at blobs of density - so just as well Nature's reviewers haven't yet 
cottoned on.

I'll add that even Kay's paper on CC1/2 (which I love, as it reminded MX of 
this question) avoided this interpretability problem -- quite reasonably, it 
can obviously keep many students busy for several years.  Or maybe not, not 
anymore, with Machine Learning now what it is.

Frank



On 20/02/2020 10:15, Nave, Colin (DLSLtd,RAL,LSCI) wrote:
Dear all,
I have received a request to clarify what I mean by threshold in my 
contribution of 17 Feb  below and then post the clarification on CCP4BB. Being 
a loyal (but very sporadic) CCP4BBer I am now doing this. My musings in this 
thread are as much auto-didactic as didactic. In other words I am trying to 
understand it all myself.

Accepting that the FSC is a suitable metric (I believe it is) I think the most 
useful way of explaining the concept of the threshold is to refer to section 
4.2 and fig. 4 of Heel and Schatz (2005), Journal of Structural Biology, 151, 
250-262. Figure 4C show an FSC together with a half bit information curve and 
figure 4D shows the FSC with a 3sigma curve.

The point I was trying to make in rather an obtuse fashion is that the choice 
of threshold will depend on what one is trying to see in the image. I will try 
and give an example related to protein structures rather than uranium hydride 
or axons in the brain. In general protein structures consist of atoms with 
similar scattering power (C, N, O with the hydrogens for the moment invisible) 
and high occupancy. When we can for example distinguish side chains along the 
backbone we have a good basis for starting to interpret the map as a particular 
structure. An FSC with a half bit threshold at the appropriate resolution 
appears to be a good guide to whether one can do this. However, if a particular 
sidechain is disordered with 2 conformations, or a substrate is only 50% 
occupied, the contribution in the electron density map is reduced and might be 
difficult to distinguish from the noise. A  higher threshold might be necessary 
to see these atoms but this would occur at a lower resolution than given by the 
half bit threshold. One could instead increase the exposure to improve the 
resolution but of course radiation damage lurks. For reporting structures, the 
obvious thing to do is to show the complete FSC curves together with a few 
threshold curves (e.g. half bit, one bit, 2 bits). This would enable people to 
judge whether the data is likely to meet their requirements. This of course 
departs significantly from the desire to have one number. A compromise might be 
to report FSC resolutions at several thresholds.

I understand that fixed value thresholds (e.g. 0.143) were originally adopted 
for EM to conform to standards prevalent for crystallography at the time. This 
would have enabled comparison between the two techniques. For many cases (as 
stated in Heel and Schatz) there will be little difference between the 
resolution given by a half bit and that given by 0.143. However, if the former 
is mathematically correct and easy to implement then why not use it for all 
techniques? The link to Shannon is a personal reason I have for preferring a 
threshold based on information content. If I had scientific “heroes” he would 
be one of them.


I have recently had a paper on x-ray imaging of biological cells accepted for 
publication. This includes

“In order to compare theory or simulations with experiment, standard methods of 
reporting results covering parameters such as the feature examined (e.g. which 
cellular organelle), resolution, contrast, depth of material (for 2D), estimate 
of noise and dose should be encouraged. Much effort has gone in to doing this 
for fields such as macromolecular crystallography but it has to be admitted 
that this is still an ongoing process.”
I think recent activity agrees with the last 6 words!



Don’t read the next bit if not interested in the relationship between the Rose 
criterion and FSC thresholds.

The recently submitted paper also includes

“A proper analysis of the relationship between the Rose criterion and FSC 
thresholds is outside the scope of this paper and would need to take account of 
factors such as the number of image voxels, whether one is in an atomicity or 
uniform voxel regime and the contrast of features to be identified in the 
image.”

This can justifiably be interpreted as 

Re: [ccp4bb] MX data processing with GPUs??

[Frank Von Delft]

Since Kay asks:

Do all of us really want and need to collect from thousands of crystals every 
synchrotron day? Are all of us really producing that many crystals? Who is?

I can't help to respond:  even if not "all of us", we certainly are!
https://www.diamond.ac.uk/Instruments/Mx/Fragment-Screening.html


We're now at <2min/crystal, including X-ray centring and a full dataset - so 
along with all Diamond's wizards, thank you Developers for making data 
processing magically fast and parallizable!

While we're at it, next deadline for proposals is April 1st:

https://www.diamond.ac.uk/Instruments/Mx/Fragment-Screening/Applying-for-XChem.html

(Apologies the shameless hijacking of the the thread...)




On 19/02/2020 12:21, Kay Diederichs wrote:

Dear Ana,

it is easy to ask the question (and I've been asked several times), but 
somewhat difficult to answer. To add to Graeme's excellent explanations:

- all developers of MX processing software have seriously considered to 
implement their algorithms on GPUs, and have decided that the effort (which is 
very significant) is not worth it, in terms of benefit for users and developers 
(who should pay them for the effort? - after all, this would not result in a 
highly cited publication!). We are aware of the fact that they are much faster 
than CPUs for specific types of calculations that are most useful for images 
where each pixel is treated in the same way - but these types of (potentially 
highly parallel) calculations do not represent a large fraction of where a MX 
data processing program spends its time, and even worse, the parallel and 
serial parts of the calculation alternate in fast succession (XDS has on the 
order of 10 parallel regions, none of which dominates the CPU time). 
Ultimately, it is the serial fraction of a program that determines its 
potential speed-up, due to Amdahl's law.

- MX data processing programs (at least XDS and DIALS) already exploit 
parallelism by using multiple CPUs at the same time; the current version of XDS 
can in principle use up to 99*99=9801 processors, and 60 machines each running 
60 threads (see below) would process a 360° dataset composed of 0.1° frames 
within seconds, if DELPHI=6.

- the recent Ryzen Threadripper 3XXX series CPUs have a significantly better 
cost/performance ratio than other processor families. A TR 3970X workstation 
can be bought for less than 5000€, and offers 64 threads. Graeme mentions AMD 
Rome; this is the server variant. The data transfer would become the 
bottleneck; to me, a cluster of workstations each equipped with two 10Gb ports 
looks attractive.

Finally, I have the feeling that speed in data collection and processing is 
over-rated. I get the impression that some (many?) people think they should 
collect a data set as quickly as the machine permits. But they may not be aware 
of the fact that the quality of the data is then not optimal. Going 10 times 
slower, and reducing the transmission to 10%, gives a resonable safety margin.

Further questions arise - does every crap crystal have to be put into the beam? 
And does every crap data set have to be processed? Do all of us really want and 
need to collect from thousands of crystals every synchrotron day? Are all of us 
really producing that many crystals? Who is? (you probably realize my lack of 
imagination by now)
I know that people who build and run synchrotron beamlines have a different 
perspective, concerning these questions, than their users. Some common sense, 
and a lot of discussion, would  benefit our community more than resorting to 
technological "solutions".

best wishes,
Kay

On Wed, 19 Feb 2020 08:08:40 +, Winter, Graeme (DLSLtd,RAL,LSCI) 
 wrote:



Dear Ana,

To follow up on the contributions from others, there are some particular 
annoyances with MX processing which differentiate it from other “big data” or 
imaging problems.

In tomographic reconstruction you have a big block of data which needs to (as a 
simplistic approximation) be transformed by a bunch of trigonometric functions 
to another big block of data. The shape of the calculation is the same 
independent of the data itself, and overall this represents a massively 
parallel computationally expensive problem, which makes it worth the cost of 
getting the data in and out of the GPU (this is not cheap) - even in this case, 
the parallelism of modern CPUs means that this is not a given. These folks are 
usually the ones who are making a lot of noise about how awesome GPU boards 
are, and for their use case this is absolutely true.

In MX we have a particularly annoying problem, as about half of the 
calculations are nicely parallel (spot finding, peak integration) and are 
memory bandwidth / CPU breadth limited and the other half (indexing, 
refinement, scaling) are not very parallel CPU speed bound, so finding the best 
CPU architecture is hard to start with. In terms of GPU, the data need to 

Re: [ccp4bb] Remember the turkey?

[Frank Von Delft]

I daresay, large segments of humanity might not consider that "unfortunate".

But since we're straying into political territory, I conclude that a number of 
subscribers have recently been on holiday and thus had the luxury of only 
far-off deadlines ;)

Sent from tiny silly touch screen

From: Rasmus Fogh 
Sent: Thursday, 2 January 2020 11:28
To: CCP4BB@JISCMAIL.AC.UK
Subject: Re: [ccp4bb] Remember the turkey?


Hi,

Unfortunately, this is not just about 'virtue signalling and posturing'.
It is (also) part of a political project - about banning certain words
so that any statement that contains them can be rejected as tainted or
evil without having to look at what it actually says. A Newspeak, basically.

Happy new year,

Rasmus Fogh

On 26/12/2019 18:46, Bernhard Rupp wrote:
> Hi Fellows - here some light Holiday entertainment (and puzzle) for you:
>
> Remember my thanksgiving posting below?  Meant as  a hoax or satire, it 
> follows the
> classical pattern of throwing postmodern Critical Theory gibberish and Social 
> Justice key words
>   (successfully deployed by Alan Sokal)
> https://en.wikipedia.org/wiki/Sokal_affair
> onto an out-of-context situation with the purpose of virtue signaling and 
> posturing on moral high ground.
>
>   Well, we just got outdone by a letter in our favorite vanity magazine, 
> Nature:
> https://www.nature.com/articles/d41586-019-03781-0
>
> The parallels are fascinating and it exactly follows the recipe developed 
> above:
> " throwing postmodern Critical Theory gibberish and Social Justice key words 
> onto an out-of-context situation
> with the purpose to signal virtue and to opportunity for posturing on moral 
> high ground"
>
> Now - is this comment (a) meant serious or (b) another successful 
> Sokal-Turkey-type hoax?
>
> Cheers, BR
>
> --
> It has come to our attention that on this bulletin board insensitive and 
> hurtful comments have
> been made towards animals with disability. Particularly concerning is the 
> display of white privilege
> and racial bias towards a minority individual  given that the turkey is also 
> referred to in German as 'Indian'.
> In view of this non-inclusive and divisive display of unwokeness, the faculty 
> Bias Response Team
> will contact you shortly and allow you to present your self-critique.
>
> We want this board to remain a safe zone inclusive of all animals, complete 
> or not.
>
> Stuffed, BR
>
> -Original Message-
> From: CCP4 bulletin board  On Behalf Of Jurgen Bosch
> Sent: Thursday, November 28, 2019 13:51
> To: CCP4BB@JISCMAIL.AC.UK
> Subject: Re: [ccp4bb] Xray-dataset usable despite low completeness ?
>
> Think of completeness with an analogy to turkey.
> Say you happen to find a one-legged turkey (incomplete by conventional 
> standard) you could still stuff it and put it in the oven and enjoy 93% of 
> the turkey. The 7% missing, who cares? Other than I like both legs of the 
> turkey :-)
>
> Happy Thanksgiving everyone
>
> Jürgen
>
> 
>
> To unsubscribe from the CCP4BB list, click the following link:
> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB=1
>



--
Rasmus H. Fogh   Tel.: +44 (0)1223 353033
Global Phasing Ltd., Fax.: +44 (0)1223 366889
Sheraton House,
Castle Park,
Cambridge CB3 0AX
United Kingdom



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Re: [ccp4bb] Remember the turkey?

[Frank Von Delft]

Those authors raise a fair point though, don't they:  if nothing else, 
"suppremacy" is an utterly daft word to use in any scientific context, 
since it brings nothing technical to the table.

Before geek triumphalism became the rage (or maybe before the need for 
grant-gaining hyperbole?), we might have selected adjectival phrases by 
referring to style guides like Strunk and White, which consistently 
emphasise informative simplicity.  But when companies get to call 
themselves "Uber" without being pilloried for it I guess we know those 
days are long gone.

phx.



On 26/12/2019 18:46, Bernhard Rupp wrote:
> Hi Fellows - here some light Holiday entertainment (and puzzle) for you:
>
> Remember my thanksgiving posting below?  Meant as  a hoax or satire, it 
> follows the
> classical pattern of throwing postmodern Critical Theory gibberish and Social 
> Justice key words
>   (successfully deployed by Alan Sokal)
> https://en.wikipedia.org/wiki/Sokal_affair
> onto an out-of-context situation with the purpose of virtue signaling and 
> posturing on moral high ground.
>
>   Well, we just got outdone by a letter in our favorite vanity magazine, 
> Nature:
> https://www.nature.com/articles/d41586-019-03781-0
>
> The parallels are fascinating and it exactly follows the recipe developed 
> above:
> " throwing postmodern Critical Theory gibberish and Social Justice key words 
> onto an out-of-context situation
> with the purpose to signal virtue and to opportunity for posturing on moral 
> high ground"
>
> Now - is this comment (a) meant serious or (b) another successful 
> Sokal-Turkey-type hoax?
>
> Cheers, BR
>
> --
> It has come to our attention that on this bulletin board insensitive and 
> hurtful comments have
> been made towards animals with disability. Particularly concerning is the 
> display of white privilege
> and racial bias towards a minority individual  given that the turkey is also 
> referred to in German as 'Indian'.
> In view of this non-inclusive and divisive display of unwokeness, the faculty 
> Bias Response Team
> will contact you shortly and allow you to present your self-critique.
>
> We want this board to remain a safe zone inclusive of all animals, complete 
> or not.
>
> Stuffed, BR
>
> -Original Message-
> From: CCP4 bulletin board  On Behalf Of Jurgen Bosch
> Sent: Thursday, November 28, 2019 13:51
> To: CCP4BB@JISCMAIL.AC.UK
> Subject: Re: [ccp4bb] Xray-dataset usable despite low completeness ?
>
> Think of completeness with an analogy to turkey.
> Say you happen to find a one-legged turkey (incomplete by conventional 
> standard) you could still stuff it and put it in the oven and enjoy 93% of 
> the turkey. The 7% missing, who cares? Other than I like both legs of the 
> turkey :-)
>
> Happy Thanksgiving everyone
>
> Jürgen
>
> 
>
> 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] Position at Diamond: XChem Beamline Scientist

[Frank Von Delft]

Dear all,
We are recruiting as permanent position a Beamline Scientist on the XChem 
fragment screening facility at Diamond.

This role is to join the XChem team to support academic and industrial users 
with experiments and service work, co-manage the XChem lab, develop new 
fragment-related methodologies, and over next few years, work on expanding the 
XChem offering beyond hit identification.

If you are a technically-minded crystallographer that enjoys teaching or 
training people, like an organised life, thrive on collaboration and like to 
see how you're making others productive, you will enjoy this job.

Besides, Diamond is incredibly collegial and has a terrific user community.

The ad is here:

https://vacancies.diamond.ac.uk/vacancy/xchem-beamline-scientist-404499.html 
(for some reason you may need to click twice on the link to make it work).

The application deadline is the 15th Dec 2019, and we wil linterview on 17th 
Dec (i.e. before Xmas).
If you have questions, contact me or Alice Douangamath 
<mailto:alice.douangam...@diamond.ac.uk>, who 
heads the facility.
Frank

--
Frank von Delft
Professor for Structural Chemical Biology

Principal Beamline Scientist: I04-1
Diamond Light Source
+44 1235 778997 (office: M,T,T)
+44 7471 026103 (mobile)

Principal Investigator: Protein Crystallography
Structural Genomics Consortium
Oxford University
+44 1865 617583 (office: W,F)



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Re: [ccp4bb] A grumble

[Frank Von Delft]

Eleanor, whom are you grumbling at?  If it's at the depositors, here's a 
counter-grumble:

How would a depositor even know

  *   know that it's "wrong"
  *   know what definition of "wrong" to work towards
  *   know that someone somewhere will care about this particular "wrongness"
  *   know that visualisation or analysis software does not elegantly deal with 
this - it is after all 2019 already

If I had to prioritise wrongnesses, I'd put top of the list that it is not as 
absolutely trivial as possible to get data into the public domain.  Which means 
working hard (even harder!) to remove all arcane things from the ecosystem.

Frank



On 10/11/2019 11:49, Eugene Osipov wrote:
Dear Eleanor,
From PDB files I see that  the structures were solved by molecular replacement 
using pdbid 1gci as a starting model. It is hard to say definitely without the 
linked paper but may be the depositors made the same error that I did some time 
ago: they solved both structures using molecular replacement instead of running 
rigid body refinement for follow up structure.
Actually, the issue with different origins is pretty common in pdb. For 
example, I searched pdb for isomorphous lysozyme structures in P43212 with unit 
cell dimensions a=b=78.5-79.3 and c=36.5-37.3 and have found 121 structures. I 
picked 6 random structures and only 2 of them have the same origin.
By the way, may be someone has a script to move several isomorphous structures 
to the same origin and rename chains according to reference structure?


пт, 8 нояб. 2019 г. в 14:02, Eleanor Dodson 
<176a9d5ebad7-dmarc-requ...@jiscmail.ac.uk>:
I have just downloaded two isomorphous coordinates from the pdb
5arb and 5arc  deposited by the same team


Tried to compare and they are on different origins.

I know it doesnt affect the crystallography
It is easily corrected

BUT it seems bad practice to me

Eleanor





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--
Evgenii Osipov
Laboratory for Biocrystallography,
Department of Pharmaceutical Sciences,
KU Leuven O



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Re: [ccp4bb] design specs/tolerances for crystallization rooms?

[Frank Von Delft]

We have the dehumidification for both 4C and 20C.  Yes, drops dry out faster, 
probably;  there are ways of mitigating, but to do it properly, in my opinion 
you need a 
Shifter<https://www.diamond.ac.uk/Instruments/Mx/Fragment-Screening/Resources.html>,
 sold by OLT<http://www.oxfordlabtech.com/> (*) -- it makes a big difference 
(manuscript due for submission).


[(*) That's a shameless plug to the extent that we developed it, meaning I 
would say that.  But the vendor OLT are selling and developing it on their own, 
and I'm a customer, not a founder.]



On 26/09/2019 12:59, Sergei Strelkov wrote:

Dear Frank and everyone,


Thanks for useful tips. Snow in liquid nitrogen has been annoying us on a 
regular basis in fact. During some synchrotron sessions, a large percentage of 
crystals were covered with snow. We could never fully figure out how to get rid 
of it, although filtering LN2 before filling the vessel for freezing seemed to 
help a bit...


Would installing a dehumidifier in a standard 20C crystallization room (where 
we mount most of our crystals) be a good idea? Any experiences there? I guess 
the downside would be that small crystallization drops would be drying more 
quickly...


Best wishes,

Sergei


Prof. Sergei V. Strelkov Laboratory for Biocrystallography Department of 
Pharmaceutical Sciences, KU Leuven O, Campus Gasthuisberg, Herestraat 49 bus 
822, 3000 Leuven, Belgium Phone: +32 16 33 08 45, mobile: +32 486 29 41 32 Lab 
pages: 
http://pharm.kuleuven.be/Biocrystallography<http://pharm.kuleuven.be/anafar>


From: CCP4 bulletin board <mailto:CCP4BB@JISCMAIL.AC.UK> 
on behalf of Frank Von Delft 
<mailto:frank.vonde...@sgc.ox.ac.uk>
Sent: Wednesday, September 25, 2019 7:03
To: CCP4BB@JISCMAIL.AC.UK<mailto:CCP4BB@JISCMAIL.AC.UK>
Subject: Re: [ccp4bb] design specs/tolerances for crystallization rooms?

My colleague Opher Gileadi gave us an excellent tip when we were designing our 
4C harvesting room, over a decade ago:  set it to 7C.  The crystals are 
unlikely to mind, but it's SO much more comfortable to be in for hours.

I seem to remember he mentioned something like a comfort inflection point as 
you approach 4C.

Install low-flow fans.  Fridge people seem to default to installing hurricane 
machines, you have to tell them that a very very small flow is enough.

Get strong light - probably even those daylight things (we don't have them).  
Being cold is miserable enough already, there's no need to compound it with 
weak light.

Vibration - that dwindles to insignificance if the air flow goes down.

Humidity - we installed (at considerable expense) a low humidity air supply - 
really hard to know just how much it helps, but a few years ago when I had it 
turned it off to help save energy, very quickly I heard complaints about snow 
in the liquid nitrogen becoming a major hassle.  So based on that set of 
anecdotes, I conclude it probably is worth having dry air.

It's much cheaper though if they can design it into the building's 
infrastructure, if it's a new building;  retrofitting turned out to be super 
expensive (in our case).

As dry as possible.  Look at and understand the psychrometric chart (google 
it):  if you're in even vaguely warm or temperate regions (or seasons), cooling 
the intake air to 4C brings it to below dew point, and then condensation and 
snow are guaranteed.

Size - make it as big as you can get away with, with lots of bench and shelf 
space.  Your students will already be miserably cold, no need for them to be 
cramped too.

Good luck!
Frank





On 24/09/2019 23:40, Scott, Emily wrote:
Anyone out there specifically design rooms for (protein) crystallization at ~22 
deg and 4 deg C?  If you have successes or failures and can share any design 
specs with regard to vibration, temperature, and humidity tolerances, it would 
be much appreciated to pass on to the architects for our new laboratory.

Sincerely,
Emily Scott

--
Emily Scott, Ph.D.
Professor, Medicinal Chemistry/Pharmacology/Biophysics
Faculty Director, BioNMR Core Lab
University of Michigan
428 Church Street
Ann Arbor, MI 48109-1065
Phone:  734-764-3530
https://pharmacy.umich.edu/people/scottee
Lab webpage:  http://scottlab.info



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Re: [ccp4bb] design specs/tolerances for crystallization rooms?

[Frank Von Delft]

My colleague Opher Gileadi gave us an excellent tip when we were designing our 
4C harvesting room, over a decade ago:  set it to 7C.  The crystals are 
unlikely to mind, but it's SO much more comfortable to be in for hours.

I seem to remember he mentioned something like a comfort inflection point as 
you approach 4C.

Install low-flow fans.  Fridge people seem to default to installing hurricane 
machines, you have to tell them that a very very small flow is enough.

Get strong light - probably even those daylight things (we don't have them).  
Being cold is miserable enough already, there's no need to compound it with 
weak light.

Vibration - that dwindles to insignificance if the air flow goes down.

Humidity - we installed (at considerable expense) a low humidity air supply - 
really hard to know just how much it helps, but a few years ago when I had it 
turned it off to help save energy, very quickly I heard complaints about snow 
in the liquid nitrogen becoming a major hassle.  So based on that set of 
anecdotes, I conclude it probably is worth having dry air.

It's much cheaper though if they can design it into the building's 
infrastructure, if it's a new building;  retrofitting turned out to be super 
expensive (in our case).

As dry as possible.  Look at and understand the psychrometric chart (google 
it):  if you're in even vaguely warm or temperate regions (or seasons), cooling 
the intake air to 4C brings it to below dew point, and then condensation and 
snow are guaranteed.

Size - make it as big as you can get away with, with lots of bench and shelf 
space.  Your students will already be miserably cold, no need for them to be 
cramped too.

Good luck!
Frank





On 24/09/2019 23:40, Scott, Emily wrote:
Anyone out there specifically design rooms for (protein) crystallization at ~22 
deg and 4 deg C?  If you have successes or failures and can share any design 
specs with regard to vibration, temperature, and humidity tolerances, it would 
be much appreciated to pass on to the architects for our new laboratory.

Sincerely,
Emily Scott

--
Emily Scott, Ph.D.
Professor, Medicinal Chemistry/Pharmacology/Biophysics
Faculty Director, BioNMR Core Lab
University of Michigan
428 Church Street
Ann Arbor, MI 48109-1065
Phone:  734-764-3530
https://pharmacy.umich.edu/people/scottee
Lab webpage:  http://scottlab.info



**
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[ccp4bb] XChem fragment screening - call for proposals - 2nd October 5pm

[Frank Von Delft]

Dear all,
This is a reminder that Diamond Light Source is accepting proposals for its 
XChem fragment screening facility, for the allocation period April to September 
2020.
The deadline is Wednesday 2nd October at 5pm (2 weeks from now).
Details on how to apply are here - we're oversubscribed, so please follow the 
instructions!

https://www.diamond.ac.uk/Instruments/Mx/Fragment-Screening/Applying-for-XChem.html

XChem is a platform for high-throughput crystal-based fragment screening, 
operational since 2015. We provide fragment libraries (or you can bring your 
own) and the pipeline entails:  rapid crystal soaking with an Echo acoustic 
liquid handler; high-throughput harvesting of hundreds of pre-soaked crystals 
using a Shifter; fully unattended data collection using dedicated beamtime on 
I04-1 beamline; and automated data integration along with tools for ligand 
detection (PanDDA) and streamlined model building (XChemExplorer).
Since April 2019, we offer both standard and Block Allocation Group (BAG) 
access.   Standard access accommodates both Tier 1 and Tier 2 proposals, for 
exploratory and ready-to-go projects respectively.
Since this summer, the FragLites library from Newcastle university (J. Med. 
Chem.20196273741-3752) is also available for users.
More information is on the XChem website:
https://www.diamond.ac.uk/Instruments/Mx/Fragment-Screening
https://www.diamond.ac.uk/Instruments/Mx/Fragment-Screening/Methods-for-Fragment-Screening.html
https://www.diamond.ac.uk/Instruments/Mx/Fragment-Screening/Fragment-Libraries.html
For more questions, please ask Alice (copied) or myself.
We are looking forward to collaborating with you!
The XChem team.




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Re: [ccp4bb] [EXTERNAL] Re: [ccp4bb] Better Beamline suggestion!

[Frank Von Delft]

We also described how to bend the loops in this article:  http://doi.org/gcb8j3 
 Figure 4 specifically.


On 21/08/2019 18:21, Edwin Pozharski wrote:

In the absence of such you can resort to carefully bending the loop or bending 
the pin (Jim Holton made a nifty device for bending the pin) while keeping the 
xtal bathed in the cold stream.


 I would also mention these

https://hamptonresearch.com/product-Adjustable-Mounted-CryoLoop-385.html



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Re: [ccp4bb] not solely pdb issue: need someone to officially settle the pdb dispute

[Frank Von Delft]

If A had deposited it to the PDB immediately, he'd have had been able to claim 
the kudos and help lots of scientists besides B.

How is it that we structural biologists still are so precious about our 
coordinates?  Or more to the point, that the supervisors still don't teach 
their students that aggressive Open Access in all domains is where everything 
is going, and besides is ethically the correct way to think of what we do with 
the money society provides us with?


On 21/08/2019 10:13, Flemming Goery wrote:
Dear all:
A has sought a job in the lab of B. B invited A for a interview with a PPT oral 
presentation, as requested B has sent the PPT on the structural biology 
research of XXX to B by e-mail, and presented in front of A and his 
postdoctoral researcher.

After interview, B requested all research documents (including detailed 
reports) on XXX to be sent by A to B by e-mail, A sent, including 2 sets of pdb 
for the same structure, one set with solvent, one without. A told B all 
intellectual property of the Documents and the research belonged to A, based on 
the regulation of A's institute.

B sought a referee from A's institute, to someone A did not agree. It seems the 
referee told B one set of PDB has been deposited (the one without solvent)

Then B did not give the offer to A. A joined Institute D, without independent 
funding for the writing (in fact, no salary to support this writing, and no fee 
for publication of this work).

Several years later, A found B's paper, i.e., the concerned paper published in 
Journal C. In the paper, B has used the information from deposited PDB for 9 
times (already a significant paprt of the paper, not to say the message from 
the other Documents sent to B by A). In the paper, it write something like, 
'based on our work on the structure of  (folowed by 4 letter pdb code)', which 
implied the structure was solved by the authors of the paper, rather than by A.

A contacted Journal C, Journal C contacted B, B claimed the deposited PDB was a 
public domain knowldge. Journal C took the action to add the reference to the 
deposited pdb in the paper.

As mentioned, the paper has mentioned and used the message from the deposited 
pdb 9 times, and in the paper the reference mark was not added to the first 
occurence of the mentioning of the deposited pdb, but added (only once for the 
9 occurences of depositation code) to a paragraph where it can be concluded 
that the authors have used the undeposited pdb with the solvent. In another 
words, although reference to the deposited pdb was added by a correction, from 
where the reference mark was added, it cannot show they have refered to the 
cited pdb, not to say the undeposited pdb with solvent which they used based on 
the paragraph information.

A's concern was that: A cannot exclude the possibility that the research in the 
paper other the part related to PDB, were fabricated, thus A request paper 
retraction as the major clain.

If cannot retratcted, A request to be the correspondence author (sometimes 
requets co-first author, sometimes request both co-first author and 
co-correspondence author), as without A's work (the PPT presentation, 2 sets of 
pdb, all documents), the work in the concerned paper cannot be done. A regard 
as having contributed to the initiation of the paper, thus A prefer to be add 
as a co-correspondence author if appropriate.

First, can the paper deserve a retraction, and second, can B deserve a 
co-author?

Flemming




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Re: [ccp4bb] AW: need someone officially settle a pdb dispute for a publication

[Frank Von Delft]

Structural genomics efforts have been putting PDBs in the public domain for 
almost 2 decades - precisely so they'd be used.  That's the whole point of the 
PDB, and open repositories:  set the data free, so it can make science happen.

"A" should be delighted that their work have actually been useful, and make a 
song and dance from the fact that science could move ahead unencumbered by 
their own (inevitable) inertia.  And even write a letter of congratulation to 
"B".  And stop spamming "C" so they can get on with evaluating the deluge of 
manuscripts.

phx


On 21/08/2019 08:54, 
herman.schreu...@sanofi.com wrote:
Dear Flemming,

As Jürgen said, what happened? Did A deposit the coordinate file in the pdb, 
but did not publish and did B take this coordinates and make a publication? Or 
did B ask A for the coordinates to have a look at and then made a publication 
without agreement of A? Did B hack the computer account of A and stole the 
coordinates?

In general, if a significant part of the publication of B were based on the 
coordinates produced by A, A should be coauthor. However, if the coordinates 
were deposited and A had ample time to write a publication, but did not do so, 
as Jürgen said, all A could ask for is to have his structure properly cited and 
acknowledged.

Something about tactics: Institute heads tend to protect their own people, so 
if the head of institute B gets an email from someone he/she does not know 
complaining about one of the people of his/hers institute, the institute head 
may not find the time to go through the trouble of a misconduct investigation 
with may harm the reputation of the institute.

However, if the head of institute A would learn that one of its people has been 
plagiarized by someone of institute B, the motivation to react will be much 
higher, especially if institute A and B are in a friendly competition.

So if I were A, I would go the head of institute A and complain about the 
academic misconduct of B and discuss what steps could be taken.

My 2 cents,
Herman



Von: CCP4 bulletin board [mailto:CCP4BB@JISCMAIL.AC.UK] Im Auftrag von Flemming 
Goery
Gesendet: Dienstag, 20. August 2019 17:46
An: CCP4BB@JISCMAIL.AC.UK
Betreff: [EXTERNAL] [ccp4bb] need someone officially settle a pdb dispute for a 
publication


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

Dear All,

A and B belong to 2 different institutes. A claimed B has used his pdb for a 
publication in Journal C. Journal C did not give the retraction, but permit 
complain related to the journal publication author issue, with the prerequisite 
journal C did not have the authority on authorship dispute. Then A has e-mailed 
to the institute head of B with academic misconduct by B as claim, the 
institute head of B did not give reply.

In this situation, can A have the journal  authorship  dispute settled by a 
neutral reviewer (Journal C view: you (A) need to reach out to the institutions 
that have authority to adjudicate on such matters, as investigation and 
adjudication on authorship claims falls outside the remit of journal editors. 
)? Who are qualified as the neutral reviewer so that the review decision can be 
submitted to Journal C?

If you believe you are qualified, or you know somebody or some organization 
qualified, please let me know and I will introduce the issue to you by separate 
e-mail (it is best not disseminated, am I right?)

Best regards.

Flemming




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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
>
>
> 
>
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[ccp4bb] Has anybody put CCP4 into a singularity container?

[Frank von Delft]

Hi all - see subject line.

If they have, or have tried and failed, can they get in touch, please?  
(Or more specifically, email Conor, conor.w...@oriel.ox.ac.uk.)


Thanks!
Frank



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[ccp4bb] 2 positions around XChem-related compound design

[Frank von Delft]

Dear all, I have two open to work on fragment/XChem-related methodology 
for structure-based compound design.


Team Leader (applications close next *Weds 1st May*):  full ad here 
<https://www.thesgc.org/careers/oxford/sgc-oxford-team-leader-xchem>, 
summary:


   /We are recruiting an experienced computational chemist or
   scientific programmer, to head the Fragalysis project for automating
   fragment hit progression, part of the XChem collaboration between
   SGC and Diamond...  The //Fragalysis
   <https://fragalysis.diamond.ac.uk/>//project leader will be tasked
   with converting the existing proof-of-concept tool into a
   production-level system that is routinely usable for analysing XChem
   results and designing and acquiring follow-up compounds. This will
   entail setting the scientific direction and priorities of the
   project through close and continuous interaction with expert and
   novice users; coordinating a growing team of scientific programmers
   and contractors; liaising with and expanding a wide and
   international set of collaborators and contributors; securing
   further funding for the project; helping supervise students; and
   developing specific methodologies of their own./


Postdoc (closing *Weds 15th May*):  full advert here 
<https://www.thesgc.org/careers/oxford/sgc-oxford-postdoctoral-research-scientist-structure-based-drug-design>, 
this is a summary:


   /This role will be tasked with the design and acquisition of
   follow-up compounds based on fragment screening hits from the Target
   Enabling Package (//www.thesgc.org/tep
   <http://www.thesgc.org/tep>//) and Ultra-DD (//www.ultra-dd.org
   <http://www.ultra-dd.org>//) programs. The successful candidate will
   coordinate experimental validation of the newly designed compounds
   with collaborating scientists in order to progress them towards
   potent molecules.
   /

Cheers
Frank


--
Prof Frank von Delft
Associate Professor Principal Investigator: Protein Crystallography
Structural Genomics Consortium
Oxford University
+44 1865 617583 (office: W,F)

Principal Beamline Scientist: I04-1
Diamond Light Source
+44 1235 778997 (office: M,T,T)
+44 7471 026103 (mobile)



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Re: [ccp4bb] High Rfree in last Shell

[Frank von Delft]

Jan, tell your reviewer to join us all in the 21st century.

Diederichs and Karplus, Science, about 2 decades ago.  (Technically, 
2012 
, 
but it really is a long long time ago now.)



On 16/04/2019 18:06, Tim Gruene wrote:

Dear Jan,

You statistics look quite solid.

R-factors are not good criteria to judge the resolution cut-off. The weighting
schemes in refinement programs have much improved since the late 1990s. A good
starting point to learn more is
Rupp's "Against Method: Table 1 -Cui Bono?", https://doi.org/10.1016/j.str.
2018.04.013

Best regards,
Tim

On Tuesday, April 16, 2019 6:57:06 PM CEST Jan van Agthoven wrote:

Hi everyone,
I’m trying to publish two structures at 3.1Å resolution with the following
refinement statistics:

Resolution range (Å)   49.2-3.1
 49.3-3.1 Rfactor (%)
24.0 (32.4)  23.4 (32.0) Rfree (%)
 26.6 (29.2)
26.3 (31.6)

Data collection
Completeness  100 (100)
   100 (100)

Redundancy6.9 (7.0)
 6.2 (6.3)

Molecules in asymmetric unit  1
 1

Average I/σ 14.1 (1.7)
  15.3 (2.0)

Rmerge (%)  14.9 (100)
 12.7 (100)

Rmeas (%)16.2 (100)
  13.9 (100)

Rsym (%)   6.2 (68.6)
 5.5 (57.1) Wilson B-factor
65.662.7

I’ve been told that the Rfree factor in the last shell are too high. Does
anyone know how I can improve these Rfree factors other then cutting the
resolution, which already is rather low?


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Re: [ccp4bb] AW: [EXTERNAL] Re: [ccp4bb] High Rfree - ice ring

[Frank von Delft]

You can use sftools to set a shell of reflections to MNF - then Refmac 
will fill those in with DFc, and that'll presumably be much better than 
having very wrong reflections.


Whether that will fix your Rfactor is a different story.

phx


On 04/04/2019 11:05, Eleanor Dodson wrote:
You cant exclude one resolution ring in REFMAC - there would be ways 
to fudge the exclusion from your current file, but much safer to use a 
data integration tool


On Thu, 4 Apr 2019 at 10:27, > wrote:


Dear Sam,

I would remove the ice ring and reprocess the data. Ice rings may
wreak havoc with scaling so at minimum you have to redo the scaling.

Best,

Herman

*Von:*CCP4 bulletin board [mailto:CCP4BB@JISCMAIL.AC.UK
] *Im Auftrag von *Sam Tang
*Gesendet:* Donnerstag, 4. April 2019 11:01
*An:* CCP4BB@JISCMAIL.AC.UK 
*Betreff:* [EXTERNAL] Re: [ccp4bb] High Rfree - ice ring


Dear Eleanor and Eric

Thanks for your replies.

Yes indeed when we looked at the plots e.g. R factor vs resln
there was a sharp peak near 3.6 - 3.8 A which is where we visibly
saw an ice ring on the image. Thus our first thought was to remove
the ic ring. (either reprocess or can we bypass this resolution
range during refinement?)

The protein is 50 kDa, two molecule in the ASU, seemingly no
obvious density was unassigned. We got ~3 total observations,
~15000 unique observations. NCS restraints was applied.

Best regards

Sam

On Thu, 4 Apr 2019 at 08:57, Eric Montemayor
mailto:montemayor.e...@gmail.com>> wrote:

That’s a rather large gap between Rwork and Rfree.  I suspect
you have mis-assigned your space group and as a result have a
large number of copies in your asymmetric unit.  Any structure
can be solved in P1, but that does not mean the true space
group is indeed P1. If you use P1 when it’s not actually P1,
you will have an unnecessarily overparamerized model, hence
the large gap between Rwork and Rfree.

Questions:

1- how many copies in your asymmetric unit in P1?

2- how many atoms in your model vs number of unique reflections?

3- if more than one copy per asymmetric unit, are you imposing
NCS restraints during refinement?

-Eric

On Wed, Apr 3, 2019 at 1:41 PM Sam Tang mailto:samtys0...@gmail.com>> wrote:

Hi everyone again

Hmmm I think we have solved a structure in P1 space, to
2.5 A. However after refinement the Rfree stuck at 33%-35%
with Rwork around 26%. The structure was solved by MR and
current model seems to fit density well. In Refmac log I
found that at the resolution corresponding to high R there
may be a solvent/ice ring. Since imosflm should be able to
exclude ice rings, I am not 100% sure whether it's the
cause to high R. But if this is actually the case, is
there a way I can exclude certain resolution bins during
Refmac (and is it an appropriate way to do so?)

PS - the data is not affected by twining or pseudosymmetry
as checked by Xtriage.

Many thanks!

Sam




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[ccp4bb] Call reminder: XChem fragment screening, NEXT WEDNESDAY

[Frank von Delft]

Dear aspiring drug discoverers

A reminder that the deadline for the next round of proposals for XChem 
fragment screening is *next Wednesday 5pm*, as part of Diamond's general 
Call for Proposals.


Full details 
<https://www.diamond.ac.uk/Instruments/Mx/Fragment-Screening/Applying-for-XChem.html> 
are on the XChem webpage 
<https://www.diamond.ac.uk/Instruments/Mx/Fragment-Screening.html>.


*Reminder: *we are now inviting a broader set of projects:

 * Two-tiered access:  if you have an exciting system but don't yet
   know how to progress it, you can ask for exploratory access ("Tier 1")
 * BAG access:  several labs and collaborations have requested
   increased flexibility, and several have been assigned Block
   Allocation Groups.  If you wish to submit this route, I suggest you
   also email me directly.

Happy screening!

Frank


--
Prof Frank von Delft
Associate Professor Principal Investigator: Protein Crystallography
Structural Genomics Consortium
Oxford University
+44 1865 617583 (office: W,F)

Principal Beamline Scientist: I04-1
Diamond Light Source
+44 1235 778997 (office: M,T,T)
+44 7471 026103 (mobile)



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Re: [ccp4bb] Is there any alternative to siliconized glass coverslips for crystallization?

[Frank Von Delft]

Or do sitting drop, it's much easier all round. Frank

Sent from tiny silly touch screen

From: Minmin Yu 
Sent: Thursday, 31 January 2019 21:42
To: CCP4BB@JISCMAIL.AC.UK
Subject: Re: [ccp4bb] Is there any alternative to siliconized glass coverslips 
for crystallization?

Yeah I used to use Fisher Scientific square plastic cover slips. Now I am using 
Sigma 22x22mm (Z36,590-4, 100 each Lot10B084279) smaller sized ones. These 
plastic ones are much more durable than the glass ones and are very easy to be 
handled. They work very well for both hanging drops or for sitting drops 
sealing with grease.

Minmin

On 31 Jan 2019, at 21:14, Daniel M. Himmel, Ph. D. 
mailto:danielmhim...@gmail.com>> wrote:

Fisher Scientific makes 22 inch square plastic cover slips, which are labeled 
"Fisherbrand Unbreakable
Cover Slips".

I and my colleagues have used them for over 15 years instead of siliconized 
glass coverslips.
Just dip each one in ethanol to clean before use, dry with an air blower, and 
use it to set up
your drops.  They work like a charm.  They come 100 to a box.  Check the Fisher 
Scientific catalog.

-Daniel


On Thu, Jan 31, 2019 at 3:17 AM Rajnandani Kashyap 
mailto:kashyap.rajnand...@gmail.com>> wrote:
Dear All
I am a PhD student who requires lots of coverslips (!!) for setting up hanging 
drop crystallization. The company sells it for a huge amount. Also there is a 
wide monetary difference between a normal siliconized coverslip and a 22mm 
siliconized circle coverslips. We tried to search for an alternative companies 
but couldn't get any one who sells coverslips with the same dimensions 
(0.19-0.22mm glass thickness and 22 mm glass diameter). Is there any 
alternative company (distribution in India) from where we can buy them for a 
reasonable price?
Thanks in advance for sparing your valuable time and efforts.

Regards
Rajnandani Kashyap
India



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Re: [ccp4bb] VERY old mtz file..

[Frank von Delft]

Congratulations, CCP4bb, you have just witnessed the longest thread on 
JISCMAIL.  38 messages (and counting, presumably).


Now we know how to troll the BB:  not even that old evergreen of where 
to cut resolution generates a fraction of this traffic.


phx


On 14/11/2018 15:54, Robbie Joosten wrote:
We'll, you never know when someone wants the data. I do know that I 
was incredibly impressed when you managed to conjure up the 
experimental data for 2ins (from 1982!) a few years ago.


Cheers,
Robbie

P.S. this was a really fun thread to read :D

On 14 Nov 2018 16:04, Eleanor Dodson 
<176a9d5ebad7-dmarc-requ...@jiscmail.ac.uk> wrote:


You are  all extremely informed and clever!!
This file is part of an old archive of haemoglobin structures from
the 1990s.
I suspect they are all generated on a VAX from lcf files when I
was "updating" the archive..

So now if I have the character I can update them all again, in the
unlikely event that someone will want to use them!


Thank you all very much
Eleanor

On Wed, 14 Nov 2018 at 14:41, Zhijie Li mailto:zhijie...@utoronto.ca>> wrote:

Hi Nick,


I think I've found the machine stamps in the ccp4 lib (Ian
Tickle directed me to the C programs folder yesterday. Thanks
Ian):


ccp4_ssydep.h

#define DFNTI_MBO       1       /**< Motorola byte order 2's
compl */
#define DFNTI_IBO       4       /**< Intel byte order 2's compl */

#define DFNTF_BEIEEE    1       /**< big endian IEEE
(canonical) */
#define DFNTF_VAX       2       /**< Vax format */
#define DFNTF_CONVEXNATIVE 5    /**< Convex native floats */
#define DFNTF_LEIEEE    4       /**< little-endian IEEE format */


Checking the numbers are quite feasible for MTZ files (not
maps because we can put anything into MRC/ccp4 map). Yes, the
idea is to try all possibilities until we can recover miller
indices that look normal.

Zhijie


*From:* Nicholas Devenish mailto:ndeven...@gmail.com>>
*Sent:* Wednesday, November 14, 2018 9:29 AM
*To:* Zhijie Li
*Cc:* CCP4BB@jiscmail.ac.uk 
*Subject:* Re: [ccp4bb] VERY old mtz file..
Hi Zhijie,

Thanks for the answer. I'd read
http://www.ccp4.ac.uk/html/mtzformat.html "The first 4
half-bytes represent the real, complex, integer and character
formats, and the last two bytes are currently unused" - and
assumed that a) formats meant size, given that it was
(4,4,4,1) in files I'd seen, though perhaps parsers don't
really seem to use this. and that b) while this doesn't
specify endian-ness, one could infer it from whether the two
unused zero-bytes came in the little-or-big end of the
integer. Otherwise there really isn't an encoded way to tell
if the file was written little or big other than guessing and
checking if the numbers are sensible?
CCP4 Program Suite: mtz format

www.ccp4.ac.uk 
Column types. All columns in an MTZ file are assigned a type,
taken from the following list. The LABIN line of a particular
job connects columns in an input MTZ file with the columns
expected by the program.




Perhaps this is a (small) flaw in the spec, though nowadays
almost everyone seems to have moved to little-endian.

Nick

On Wed, Nov 14, 2018 at 2:13 PM Zhijie Li
mailto:zhijie...@utoronto.ca>> wrote:
>
> Hi Nick,
>
>
> I guessed the machine stamp from MRC/CCP4 format description
- half byte 01 means BE, half byte 04 means LE. Are these only
applicable to intel machines? How are other machine
architectures indicated? I do not know. We probably can find
the authoritative answer from the CCP4 library, just need a
little bit more time...
>
>
> The machine stamp itself should not be affected by the
machine's architecture, because it needs to be read before the
program knows what the architecture is. Therefore it should be
a string instead of a number. In the MRC/CCP4 map
specification, it says that only the first two bytes are
used.  I had seen some home-brew programs taking shortcuts by
using the int value of the machine stamp word, and I thought
that was smart. Now I realise that this practice has the risk
of failing on non-intel machines. So, if it is meant to be
half-bytes, interpret it as half bytes!
>
>
> Zhijie
>
>
>
> 
> From: 

Re: [ccp4bb] Very strange LINK cards appearing in recent structures

[Frank von Delft]

Sorry, that was menat to be:  "... force us _to deposit_ /full details/"

On 12/11/2018 09:49, Frank von Delft wrote:


While you're at it, can you force us /full details/ of restraints 
used, whether it's the particular CCP4 library release, the CIF of the 
ligand, or the non-standard links?


As far as I understand refinement, they're as least as important a 
determinant of the final structure as the observed data.


phx


On 12/11/2018 09:44, John Berrisford wrote:

Dear all

We (the wwPDB) are actively looking into and correcting link records in the
PDB. A lot of the recent re-releases were (and will continue to be) to
correct links in existing PDB entries. I removed over 10,000 incorrect links
in one sitting!

We are also working to ensure that incorrect link records do not get added
into entries during annotation and part of this process is working with
developers of refinement packages to ensure that we receive links as they
were used in refinement in a standard format that we can read.

As Robbie mentioned, if you do find any entries with incorrect link records
then do please let us know so we can correct them.

Regards

John
PDBe

-Original Message-
From: CCP4 bulletin board [mailto:CCP4BB@JISCMAIL.AC.UK] On Behalf Of
Clemens Vonrhein
Sent: 12 November 2018 07:32
To:CCP4BB@JISCMAIL.AC.UK
Subject: Re: [ccp4bb] Very strange LINK cards appearing in recent structures

Dear all,

we also have a lot of "fun" with LINK records when taking deposited PDB
structures into BUSTER refinement. Sometimes (but not often) there are
missing LINK records, but the vast number of problems is due to erroneous
LINK records added by annotation software it seems (based on a cut-off of
3.5A apparently).

Correcting those issues once reported is one option, but maybe revisiting
the idea about auto-generating LINK records during deposition would be
beneficial. At the end of refinement the various packages will have all
required and no wrong/additional LINK records in the final PDB file - and
deposition software should probably take those as-is without automatically
rewriting/adding/removing any (while still present a note/warning to
depositor about potentially missed LINK records according to annotation
software). This would most likely result in much fewer LINK problems in
deposited PDB structures.

As the format guide says:

   The LINK records specify connectivity between residues that is not
   implied by the primary structure.

and specifically mentions bonds (not hydrogen bonds or salt-bridges):
https://www.wwpdb.org/documentation/file-format-content/format33/sect6.html#
LINK

Cheers

Clemens
   


On Sun, Nov 11, 2018 at 07:31:55PM +, Robbie Joosten wrote:

Erroneous LINK records happen quite a lot and used to be the combination

of aggressive annotation software and depositors not paying attention to the
comments from the annotators. They make up a large fraction of the bug
reports I have sent to the PDB over the years. They are usually fixed very
quickly by the annotators, as long as someone takes time to report them.

This case looks like an error in a refinement program which nevertheless

should have been caught by the depositors. What I would like to know is
whether the deposited, pre-annotation model had the LINKs or not.

LINKs are a bloody nightmare when it comes to annotation. At the moment

there is no record keeping of targets and chemical modifications in a
dictionary on the side of the PDB so there is also no standardisation. IMO
mmCIF makes it easier to store the restraints with the coordinates, but
there is still no neat mapping by LINK identfiers the way the LINKR format
works in Refmac. I think that is a missed opportunity.

Sorry for the rant, I blame the F1.

Cheers,
Robbie


Op 11 nov. 2018 19:47 schreef Tristan Croll:

I've seen instances like the following in roughly half a dozen
deposited structures over the past year or so. Each time I've
contacted the authors, who've been just as mystified as me by them -
and certainly didn't add them on purpose. It seems to me that some
fairly commonly-used package is erroneously turning clashes into LINK
cards in some circumstances. I just found the following clearly wrong
LINKs in 6caj (deposited January this year):

LINK CD2 PHE I 266 CG2 THR I 272 1555   1555
   1.47
LINK CE2 PHE I 266 CG2 THR I 272 1555   1555
   1.47

... which looks like the attached image. The same bonds are also
specified in the mmCIF file, for the record.

Anyone have any clue?

Best regards,

Tristan

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Re: [ccp4bb] Very strange LINK cards appearing in recent structures

[Frank von Delft]

While you're at it, can you force us /full details/ of restraints used, 
whether it's the particular CCP4 library release, the CIF of the ligand, 
or the non-standard links?


As far as I understand refinement, they're as least as important a 
determinant of the final structure as the observed data.


phx


On 12/11/2018 09:44, John Berrisford wrote:

Dear all

We (the wwPDB) are actively looking into and correcting link records in the
PDB. A lot of the recent re-releases were (and will continue to be) to
correct links in existing PDB entries. I removed over 10,000 incorrect links
in one sitting!

We are also working to ensure that incorrect link records do not get added
into entries during annotation and part of this process is working with
developers of refinement packages to ensure that we receive links as they
were used in refinement in a standard format that we can read.

As Robbie mentioned, if you do find any entries with incorrect link records
then do please let us know so we can correct them.

Regards

John
PDBe

-Original Message-
From: CCP4 bulletin board [mailto:CCP4BB@JISCMAIL.AC.UK] On Behalf Of
Clemens Vonrhein
Sent: 12 November 2018 07:32
To: CCP4BB@JISCMAIL.AC.UK
Subject: Re: [ccp4bb] Very strange LINK cards appearing in recent structures

Dear all,

we also have a lot of "fun" with LINK records when taking deposited PDB
structures into BUSTER refinement. Sometimes (but not often) there are
missing LINK records, but the vast number of problems is due to erroneous
LINK records added by annotation software it seems (based on a cut-off of
3.5A apparently).

Correcting those issues once reported is one option, but maybe revisiting
the idea about auto-generating LINK records during deposition would be
beneficial. At the end of refinement the various packages will have all
required and no wrong/additional LINK records in the final PDB file - and
deposition software should probably take those as-is without automatically
rewriting/adding/removing any (while still present a note/warning to
depositor about potentially missed LINK records according to annotation
software). This would most likely result in much fewer LINK problems in
deposited PDB structures.

As the format guide says:

   The LINK records specify connectivity between residues that is not
   implied by the primary structure.

and specifically mentions bonds (not hydrogen bonds or salt-bridges):
https://www.wwpdb.org/documentation/file-format-content/format33/sect6.html#
LINK

Cheers

Clemens
   


On Sun, Nov 11, 2018 at 07:31:55PM +, Robbie Joosten wrote:

Erroneous LINK records happen quite a lot and used to be the combination

of aggressive annotation software and depositors not paying attention to the
comments from the annotators. They make up a large fraction of the bug
reports I have sent to the PDB over the years. They are usually fixed very
quickly by the annotators, as long as someone takes time to report them.

This case looks like an error in a refinement program which nevertheless

should have been caught by the depositors. What I would like to know is
whether the deposited, pre-annotation model had the LINKs or not.

LINKs are a bloody nightmare when it comes to annotation. At the moment

there is no record keeping of targets and chemical modifications in a
dictionary on the side of the PDB so there is also no standardisation. IMO
mmCIF makes it easier to store the restraints with the coordinates, but
there is still no neat mapping by LINK identfiers the way the LINKR format
works in Refmac. I think that is a missed opportunity.

Sorry for the rant, I blame the F1.

Cheers,
Robbie


Op 11 nov. 2018 19:47 schreef Tristan Croll :

I've seen instances like the following in roughly half a dozen
deposited structures over the past year or so. Each time I've
contacted the authors, who've been just as mystified as me by them -
and certainly didn't add them on purpose. It seems to me that some
fairly commonly-used package is erroneously turning clashes into LINK
cards in some circumstances. I just found the following clearly wrong
LINKs in 6caj (deposited January this year):

LINK CD2 PHE I 266 CG2 THR I 272 1555   1555
   1.47
LINK CE2 PHE I 266 CG2 THR I 272 1555   1555
   1.47

... which looks like the attached image. The same bonds are also
specified in the mmCIF file, for the record.

Anyone have any clue?

Best regards,

Tristan

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Re: [ccp4bb] CC work / free

[Frank von Delft]

Does any refinement software automatically do the CC* resolution 
exploration ("paired refinement") that Kay did in the original paper?  
Now that /would/ be fantastically useful.



On 08/11/2018 12:44, Pavel Afonine wrote:

Clément,
I'm guessing this is because it isn't clear what CCwork/CCfree can 
tell you that Rwork/Rfree can not. Needless to say we all more or less 
have a good idea about what the ok values for Rwork, Rfree and 
Rfree-Rwork (as function of resolution) while it is much less clear 
(to me at least) when it comes to CCwork/CCfree.
I think phenix.refine used to report CCwork/CCfree in some releases 
but I removed it as useless.

All the best,
Pavel

On Thu, Nov 8, 2018 at 8:16 PM Clement Degut 
<26de0a160250-dmarc-requ...@jiscmail.ac.uk 
> wrote:


Hi all,

This probably have already be discussed, but can't find trace of it :
Is there any reason I am not aware of that refinement software
(thinking of both phenix and refmac) do not output CC work / free ?
We all accepted CC 1/2 for resolution cut (whether it's 30 or 10
%) which tend to lead to high Rfree ( last shells having very poor
phases), at least high overall R free in regard to the majority
same resolution structures as they been refined with I/sig > 3.
Which in return push people to cut resolution AFTER refinement
which obviously drastically decrease the R free and catapult your
structure from worst of the PDB to best of the PDB. It should
never be done but it is nonetheless.
How to blame a "non expert"  to do that when changing the
resolution from 1.49 to 1.5 change your Rfree by 2% (yes it
exaggerated but you get the idea).
Now it seems to me -but I may be very wrong as I am far from
expert in the arcane math of these- that CC work and free would be
more agnostic to this resolution cut off problem, as we compare it
to the CC* value anyway ? thought it will never start to be used
if refinement software don't output it as a standard (not talking
about completely replacing Rfree here as it is obviously useful).
Would CC work/free be a bad appreciation of the refinement process ?

Thanks

Clément



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Re: [ccp4bb] help needed with a rabbit-head-shaped blob

[Frank Von Delft]

It's more a Pacman ghost, innit??

Sent from Nine

From: Deborah Harrus 
Sent: Friday, 2 November 2018 21:25
To: CCP4BB@JISCMAIL.AC.UK
Subject: [ccp4bb] help needed with a rabbit-head-shaped blob


Dear all,

I came across an unidentified rabbit-head-shaped blob and would need help for 
its identification. There are 2 molecules of protein per asymmetric unit but 
there are some differences between the two chains. The blob is located in 
between the two chains, and is surrounded by residues Asp, Pro, and Val.

The protein, a glycosyltransferase, was expressed in E. coli BL21(DE3) and 
purified on Ni-NTA followed by gel filtration. The purification buffer included 
Sodium phosphate and NaCl. The crystallization condition had Bis-Tris, ammonium 
acetate and PEG 2, and glycerol was used as cryoprotectant. From the size, 
bis-tris was the most probable, but I have tried to fit it and it is not 
convincing.

The structure is 1.6 angstrom resolution and this is the only thing left to be 
done, it's driving me crazy!

Pictures attached show the face, bottom and top of the head. 2Fo-Fc is at 1.1 
sigma, Fo-Fc at 3 sigmas.

Many thanks in advance for your suggestions!

Regards,
Deborah.



=
Deborah Harrus, PhD.

University of Oulu / Faculty of Biochemistry and Molecular Medicine
Aapistie 7 A, 90220 Oulu
Finland

office: F123B
email: deborah.har...@oulu.fi
phone: +358 50 3502387 / +358 44 2386351
http://www.oulu.fi/fbmm/node/20603
=



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[ccp4bb] Deadline for Diamond XChem proposals next Wednesday

[Frank von Delft]

Dear aspiring drug discoverers

A reminder that the deadline for the next round of proposals for XChem 
fragment screening is *next Wednesday*, as part of Diamond's general 
Call for Proposals.


Full details 
<https://www.diamond.ac.uk/Instruments/Mx/Fragment-Screening/Applying-for-XChem.html> 
are on the XChem webpage 
<https://www.diamond.ac.uk/Instruments/Mx/Fragment-Screening.html>.


*NEW*:  we are now inviting a broader set of projects:

 * Two-tiered access:  if you have an exciting system but don't yet
   know how to progress it, you can ask for exploratory access ("Tier 1")
 * BAG access:  several labs and collaborations have requested
   increased flexibility, and they can now apply as Block Allocation
   Groups.  If you wish to submit this route, I suggest you also email
   me directly.

Happy screening!

Frank


--
Prof Frank von Delft
Associate Professor Principal Investigator: Protein Crystallography
Structural Genomics Consortium
Oxford University
+44 1865 617583 (office: W,F)

Principal Beamline Scientist: I04-1
Diamond Light Source
+44 1235 778997 (office: M,T,T)
+44 7471 026103 (mobile)



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[ccp4bb] Recruiting fragment/XChem crystallographers

[Frank von Delft]

Hi all -

We have vacancies at SGC (in my and Prof. Paul Brennan's groups) for 
crystallographers interested in driving a series of new genetically 
validated targets (inflammation and Alzheimers) from gene to XChem 
fragment screening and beyond to potency, and helping figure out how to 
do all of this a lot better than we currently can.


Link is here 
<https://www.recruit.ox.ac.uk/pls/hrisliverecruit/erq_jobspec_version_4.display_form?p_refresh_search=Y_internal_external=E_form_profile_detail=_display_in_irish=N_recruitment_id=136811_company=10_process_type=_applicant_no=_display_apply_ind=Y>, 
and deadline is in two weeks (October 5th).


Frank

--
Prof Frank von Delft
Associate Professor
Principal Investigator: Protein Crystallography
Structural Genomics Consortium
Oxford University
+44 1865 617583 (office: W,F)

Principal Beamline Scientist: I04-1
Diamond Light Source
+44 1235 778997 (office: M,T,T)
+44 7471 026103 (mobile)





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Re: [ccp4bb] collective term for hydrogen bonds and salt bridges

[Frank von Delft]

Okay.  The original poster asked about hydrogen bonds and electrostatic 
interactions.  That's what I was referring to when I mentioned 
"enthalpic interactions".


And I think you're saying the same thing - which is cool.

On 19/09/2018 15:06, Stefano Trapani wrote:
Hi Frank  > > I mean that, in my opinion, the term "enthalpic interaction" is 
not > appropriate to describe the hydrophobic effect, since the latter 
is > mainly driven by changes in the (system) entropy, not enthalpy. > > 
Table1 of the cited paper reports the thermodynamic functions for > 
transferring some nonpolar solutes from a few organic solvents to > 
water. The author says that: "The data collected in Table 1 clearly > 
show that the thermodynamic barrier to the solution process is > 
entropic rather than enthalpic". > > Also, after a brief description of 
two theoretical models (the > cavity-based model and the clathrate cage 
model) the author states: > "It is important to point out that both the 
cavity-based model and > the clathrate cage model rest upon the fact 
that the hydrophobic > effect is entropy, not enthalpy driven. The 
models differ only in how > they explain the source of the entropy 
loss." > > Best > > Stefano > > > > Le 2018-09-19 14:41, Frank von Delft 
a écrit : >> >> Hi Stefano - could you elaborate? >> >> Certainly the 
medicinal chemists go on a great deal about how >> deltaH balances 
deltaS and how it's bloody hard to know what is >> what even when you 
try to measure it. Which is what that abstract >> also goes on about. >> 
>> >> >> On 19/09/2018 10:54, Stefano Trapani wrote: >>> >>> Le 
2018-09-19 11:59, Frank von Delft a écrit : >>> >>> I believe medicinal 
chemists do indeed talk about "enthalpic >>> interactions". Frank >>> 
>>> Not a good choice either (à mon avis ...) >>> >>> >>> >>> >>> >>> 
The Real Reason Why Oil and Water Don't Mix >>> >>> Todd P. Silverstein 
Journal of Chemical Education *1998* /75/ >>> (1), 116 >>> >>> DOI: 
10.1021/ed075p116 >>> >>> https://pubs.acs.org/doi/abs/10.1021/ed075p116 
>>> >>> >>> Stefano >>> >>> >>> >>> On 19/09/2018 10:40, Stefano 
Trapani wrote: >>> >>> Le 2018-09-18 19:31, Daniel M. Himmel, Ph. D. a 
écrit : >>> >>> (where hydrophobic interactions result from van der 
Waals forces >>> in an aqueous environment). >>> >>> Hi >>> >>> I am not 
sure that, if one is to give a concise definition of >>> hydrophobic 
"interactions", this would be a convenient one, >>> because it may lead 
someone to identify vdW forces as the main >>> factor that maintains 
apolar aggregated molecules together in >>> aqueous environment. I have 
seen many students (and PhD's) >>> believing to the equality: 
hydrophobic 'forces'=vdW forces (and >>> not understanding, for example, 
that the side chains of a Ser and >>> an Ile can also establish vdW 
interactions). >>> >>> It is true that apolar groups that aggregate 
establish van der >>> Waals interactions (like any molecule in contact 
with another >>> one) but these microscopic (real) forces are not (as 
far as I >>> know) the main reason of aggregation in aqueous 
environment. >>> >>> The hydrophobic effect seem to be of a mainly 
entropic nature >>> (and it has much more to do with hydrogen bonds than 
van der >>> Waals forces): >>> >>> 
https://en.wikipedia.org/wiki/Hydrophobic_effect#Cause >>> >>> 
https://en.wikipedia.org/wiki/Entropic_force#Hydrophobic_force >>> >>> 
Being mainly of an entropic nature, hydrophobic "contacts" are >>> not 
the direct result of real microscopic "forces" that act >>> between 
apolar groups. The terms "forces" and "interactions" in >>> widely used 
expressions like "hydrophobic forces" and >>> "hydrophobic interactions" 
are somehow misleading. >>> >>> Best >>> >>> --- Stefano Trapani >>> >>> 
Maître de Conférences >>> 
http://www.cbs.cnrs.fr/index.php/fr/personnel?PERS=Stefano%20Trapani >>> 
>>> -
Centre de Biochimie Structurale (CBS) 29 rue de Navacelles 34090  >>> MONTPELLIER Cedex, France >>> >>> Tel : +33 (0)4 67 41 77 29 Fax : 
+33 (0)4 67 4

Re: [ccp4bb] collective term for hydrogen bonds and salt bridges

[Frank von Delft]

Hi Stefano - could you elaborate?

Certainly the medicinal chemists go on a great deal about how deltaH 
balances deltaS and how it's bloody hard to know what is what even when 
you try to measure it.  Which is what that abstract also goes on about.



On 19/09/2018 10:54, Stefano Trapani wrote:


Le 2018-09-19 11:59, Frank von Delft a écrit :

I believe medicinal chemists do indeed talk about "enthalpic 
interactions".  Frank



Not a good choice either (à mon avis ...)


The Real Reason Why Oil and Water Don't Mix

Todd P. Silverstein
Journal of Chemical Education *1998* /75/ (1), 116

DOI: 10.1021/ed075p116

https://pubs.acs.org/doi/abs/10.1021/ed075p116

Stefano

On 19/09/2018 10:40, Stefano Trapani wrote:


Le 2018-09-18 19:31, Daniel M. Himmel, Ph. D. a écrit :

(where hydrophobic interactions result from van der Waals forces
in an aqueous environment).

Hi

I am not sure that, if one is to give a concise definition of 
hydrophobic "interactions", this would be a convenient one, because 
it may lead someone to identify vdW forces as the main factor that 
maintains apolar aggregated molecules together in aqueous 
environment. I have seen many students (and PhD's) believing to the 
equality: hydrophobic 'forces'=vdW forces (and not understanding, 
for example, that the side chains of a Ser and an Ile can also 
establish vdW interactions).


It is true that apolar groups that aggregate establish van der Waals 
interactions (like any molecule in contact with another one) but 
these microscopic (real) forces are not (as far as I know) the main 
reason of aggregation in aqueous environment.


The hydrophobic effect seem to be of a mainly entropic nature (and 
it has much more to do with hydrogen bonds than van der Waals forces):


https://en.wikipedia.org/wiki/Hydrophobic_effect#Cause

https://en.wikipedia.org/wiki/Entropic_force#Hydrophobic_force

Being mainly of an entropic nature, hydrophobic "contacts" are not 
the direct result of real microscopic "forces" that act between 
apolar groups. The terms "forces" and "interactions" in widely used 
expressions like "hydrophobic forces" and "hydrophobic interactions" 
are somehow misleading.


Best

---
Stefano Trapani

Maître de Conférences
http://www.cbs.cnrs.fr/index.php/fr/personnel?PERS=Stefano%20Trapani
-
Centre de Biochimie Structurale (CBS)
29 rue de Navacelles
34090 MONTPELLIER Cedex, France

Tel : +33 (0)4 67 41 77 29
Fax : +33 (0)4 67 41 79 13
-
Université de Montpellier
CNRS UMR 5048
INSERM UMR 1054
-

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Re: [ccp4bb] collective term for hydrogen bonds and salt bridges

[Frank von Delft]

I believe medicinal chemists do indeed talk about "enthalpic 
interactions".  Frank


On 19/09/2018 10:40, Stefano Trapani wrote:


Le 2018-09-18 19:31, Daniel M. Himmel, Ph. D. a écrit :

(where hydrophobic interactions result from van der Waals forces in 
an aqueous environment).



Hi

I am not sure that, if one is to give a concise definition of 
hydrophobic "interactions", this would be a convenient one, because it 
may lead someone to identify vdW forces as the main factor that 
maintains apolar aggregated molecules together in aqueous environment. 
I have seen many students (and PhD's) believing to the equality: 
hydrophobic 'forces'=vdW forces (and not understanding, for example, 
that the side chains of a Ser and an Ile can also establish vdW 
interactions).


It is true that apolar groups that aggregate establish van der Waals 
interactions (like any molecule in contact with another one) but these 
microscopic (real) forces are not (as far as I know) the main reason 
of aggregation in aqueous environment.


The hydrophobic effect seem to be of a mainly entropic nature (and it 
has much more to do with hydrogen bonds than van der Waals forces):


https://en.wikipedia.org/wiki/Hydrophobic_effect#Cause

https://en.wikipedia.org/wiki/Entropic_force#Hydrophobic_force

Being mainly of an entropic nature, hydrophobic "contacts" are not the 
direct result of real microscopic "forces" that act between apolar 
groups. The terms "forces" and "interactions" in widely used 
expressions like "hydrophobic forces" and "hydrophobic interactions" 
are somehow misleading.


Best

---
Stefano Trapani

Maître de Conférences
http://www.cbs.cnrs.fr/index.php/fr/personnel?PERS=Stefano%20Trapani
-
Centre de Biochimie Structurale (CBS)
29 rue de Navacelles
34090 MONTPELLIER Cedex, France

Tel : +33 (0)4 67 41 77 29
Fax : +33 (0)4 67 41 79 13
-
Université de Montpellier
CNRS UMR 5048
INSERM UMR 1054
-

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[ccp4bb] Vacancy at Diamond: Senior Support Scientist (I04-1, XChem)

[Frank von Delft]

Hello all

I'm recruiting a Senior Support Scientist to my beamline I04-1 at 
Diamond.  Apart from MX user support (obviously), the position will help 
work on automating more complicated kinds of data collection and 
figuring out how to get more data faster, especially for XChem fragment 
screening but also beyond.


Technically-minded crystallographers that enjoy teaching or training 
people, but also like hands-on wires-and-cables style work and/or 
mucking around with programming or scripting, will enjoy this job. 
Diamond is incredibly collegial, with a terrific user community.


The ad is here:
https://vacancies.diamond.ac.uk/vacancy/senior-support-scientist-356961.html

Frank


--
Prof Frank von Delft

Principal Beamline Scientist: I04-1
Diamond Light Source
+44 1235 778997 (office: M,T,T)
+44 7471 026103 (mobile)

Associate Professor Principal Investigator: Protein Crystallography
Structural Genomics Consortium
Oxford University
+44 1865 617583 (office: W,F)



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Re: [ccp4bb] Should we still keep copies of all raw data?

[Frank von Delft]

Are the LHC researchers that analyse the detector readout on the fly 
without ever storing the data also guilty of malpractice? Hardcore.


Just a few more years, a few more Eiger detectors, a few more serial 
beamlines, a few more clusters and clouds, and a few more DIALS-style 
programmers, before MX too throws in the towel and starts trusting 
real-time processing and stops bothering with storing "raw" images.


phx.



On 13/07/2018 11:07, John R Helliwell wrote:

Dear Sergei,
Re “all”. As a researcher my perspective is that one’s funding agency 
requirement for a data management plan will be the core of what you 
would need to follow. Your employer may have additional policies and 
requirements placed on you as an employee. Eg the UK funding agency 
EPSRC requires data be retained for 10 years. My employer, University 
of Manchester, has a policy which regards data loss as research 
malpractice.
Central facility data retention policies vary from facility to 
facility so you would need to check ie for the ones you use.
For publication IUCr encourages raw data underpinning a publication be 
archived and its doi cited. That doi can also be entered into the 
relevant PDB deposition.

Best wishes,
John


Emeritus Professor John R Helliwell DSc

On 13 Jul 2018, at 10:30, Sergei Strelkov > wrote:



Dear All,


I believe this question may be of some interest.

In the past, we always stored all raw data ever collected by the lab.

With the recent advances, such as

(a) automated/on-the-fly processing offered by some (European) 
synchrotrons, and


(b) an ongoing discussion on centralized raw data archiving,

I wonder if it is time to revise the strict policy of keeping all data

(before we invest in a new NAS system... )


Best wishes,

Sergei


Prof. Sergei V. Strelkov Laboratory for Biocrystallography Department 
of Pharmaceutical Sciences, KU Leuven




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Re: [ccp4bb] PanDDA error revisiting old run

[Frank von Delft]

Hi Chris - that said, it is probably a better idea to repeat the old 
analyses with the new version, even if that costs more time.


Frank


On 20/06/2018 11:42, Pearce, N.M. (Nick) wrote:

Hi,

Yes, it is the case that newer pandda version may not be compatible with old 
pandda analyses. You’ll have to downgrade to the version you used originally.

Thanks,
Nick


On 20 Jun 2018, at 12:17, Chris Richardson  wrote:

One of our group has been using the newly updated PanDDA (0.2.12 in ccp4 
7.0.058) to look at some data previously processed with PanDDA.  It dies with 
an error on unpickling a pickle file (see errors below).

My guess is that changes have left it unable to read some pickle files from 
previous versions.  I’ve tried running pandda.analyse on the tutorial data and 
it completes without errors.

Can anyone shed some light on this?

TIA,

Chris

---%<---

PanDDA is running on Ubuntu 16.0.4 LTS with CCP4 7.0.058.  The command was:

pandda.analyse data_dirs="/work//foop/" out_dir="//pandda/pandda_analyse" 
min_build_datasets=30 max_new_datasets=500 grid_spacing=0.5 cpus=8 events.order_by=cluster_size pdb_style='pandda_in_*.pdb' 
mtz_style='pandda_in_*_map_coeffs.mtz' recalculate_statistical_maps=no existing_datasets=reprocess 
reference.pdb="/work//pandda/pandda_analyse/reference/reference.pdb" 
reference.mtz="/work//pandda/pandda_analyse/reference/reference.mtz"

The error is:

<…>
Checking for existing analyses
->>>
Looking for pickled files from previous runs in: pickled_data
-> Loading reference grid
Unpickling File: pickled_data/grid.pickle
-> Loading reference dataset
Unpickling File: pickled_data/reference_dataset.pickle
Runtime: 00 hours:00 minutes:00 seconds

## <~~~> 
###
### PanDDA exited with an error 
 ###
## <~~~> 
###

->>>

Traceback (most recent call last):
  File 
"/common/app/ccp4/7.0.0/ccp4-7.0/lib/python2.7/site-packages/panddas-0.2.12-py2.7.egg/pandda/analyse/__init__.py",
 line 1081, in run
pandda_analyse_main(pandda=pandda)
  File 
"/common/app/ccp4/7.0.0/ccp4-7.0/lib/python2.7/site-packages/panddas-0.2.12-py2.7.egg/pandda/analyse/__init__.py",
 line 1020, in pandda_analyse_main
pandda.run_analysis_init()
  File 
"/common/app/ccp4/7.0.0/ccp4-7.0/lib/python2.7/site-packages/panddas-0.2.12-py2.7.egg/pandda/analyse/classes.py",
 line 771, in run_analysis_init
self.load_pickled_objects()
  File 
"/common/app/ccp4/7.0.0/ccp4-7.0/lib/python2.7/site-packages/panddas-0.2.12-py2.7.egg/pandda/analyse/classes.py",
 line 821, in load_pickled_objects

self.datasets.set_reference(dataset=self.unpickle(self.pickle_handler.get_file('reference_dataset')))
  File 
"/common/app/ccp4/7.0.0/ccp4-7.0/lib/python2.7/site-packages/panddas-0.2.12-py2.7.egg/giant/manager.py",
 line 82, in unpickle
return easy_pickle.load(pickle_file)
  File 
"/common/app/ccp4/7.0.0/ccp4-7.0/lib/py2/site-packages/cctbx_project/libtbx/easy_pickle.py",
 line 80, in load
return cPickle.loads(_open(file_name, "rb").read())
AttributeError: 'module' object has no attribute 'ElectronDensityMap'

->>>

## <~~~> 
###
### PanDDA exited with an error 
 ###
## <~~~> 
###
--
Dr Chris Richardson :: Sysadmin, structural biology, icr.ac.uk





The Institute of Cancer Research: Royal Cancer Hospital, a charitable Company 
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Re: [ccp4bb] Compound with flexible conformation but nM Kd

[Frank von Delft]

Long alkyl chains tend to bad things to hang onto any compound, if it's 
to be biologically useful.  Go consult your friendly local medicinal 
chemist, chances are they'll freak out.



Anyway, long alkyl chains LOVE binding to surfaces, which is of course 
exactly the sort of thing that generates the signal in SPR.  Go consult 
your friendly local SPR ligand-binding expert, chances are they'll point 
to a number of red flags in your readout - not least the fact that it's 
a massive outlier in the chemical series (if I understood your correctly.)



Frank



On 27/04/2018 10:00, Barone, Matthias wrote:


we also do structure-activity relationship and rational drug design. 
And I agree with Christian: never rely on one single method and try to 
include a homogenous assay, such as ITC or FT. you mention a tyrosine 
involved in the binding pocket. Did you try to track the Tyr in FT?


best, matthias


*From:* CCP4 bulletin board  on behalf of 
Christian Roth 

*Sent:* Friday, April 27, 2018 9:00:03 AM
*To:* CCP4BB@JISCMAIL.AC.UK
*Subject:* Re: [ccp4bb] Compound with flexible conformation but nM Kd
Anectodal evidence I have heard from colleagues working with things, 
which are immobilized is that the measured Kd value on the surface can 
be wildly different from what is measured in solution. A superbinder 
on a surface might not be as good in solution. There seems still a lot 
of debate why that is.


Cheers
Christian

On Fri, Apr 27, 2018 at 5:07 AM, WENHE ZHONG 
> 
wrote:


Hi Philippe,

The affinity was measured by SPR where we immobilized the protein
on the chip. One thing I forgot to mention is that the association
rate (kon) shown in SPR experiment for this compound is faster
(>10-fold faster) compared to other analogues with similar koff.
There is a pi-pi interaction between the scaffold structure and
the protein (tyrosine ring). Is it possible that the hydrophobic
substituent could facilitate the formation of this pi-pi
interaction but not necessary to involve in the interaction? Thanks.

Kind regards,
Wenhe


On Apr 27, 2018, at 1:50 AM, DUMAS Philippe (IGBMC)
> wrote:


Le Jeudi 26 Avril 2018 16:50 CEST, WENHE ZHONG
> a écrit:

Just to be sure: how was the nM affinity evaluated ? By in vitro
measurements, or by obtaining an IC50 by tests on cells ?
Of course, if you are mentioning an IC50, you may have a
measurement of the efficacy of drug entrance in the cells, not
just of specific binding to your protein target.
Philippe D.


Dear Community,

A little bit out of topic here. We are applying the
structure-based approach to design compounds that can bind our
protein target. We have synthesized a series of analogues based
on the same scaffold with different substituents at one
particular site. The most potent analogue (nM Kd) has a long
alkyl chain substituent. We thought this hydrophobic substituent
should have strong interactions with the target protein leading
to nM range affinity. However, crystal structures show very weak
densities for this substituent and no obvious interaction
between the substituent and the target protein, suggesting that
this long alkyl chain substituent is flexible without binding to
the protein. This binding site is relatively negative charged
according to the electrostatic potential analysis.

So it is a puzzle to me that how this dynamic and hydrophobic
alkyl chain substituent can lead the compound to achieve nM
affinity (>10-fold better than any other substituent) — in
particular the binding site is not hydrophobic and no
interaction is found between the substituent and the protein.

Anything I have miss here that can increase the binding affinity
without interacting with the target?

Thanks.

Kind regards,
Wenhe

Re: [ccp4bb] (arcane) How to generate complete set of indices at low res

[Frank von Delft]

Thanks James, that's a very useful steer - this is definitely an easy 
thing to get mixed up with, we can go scratch around there.


I now vaguely recall an ancient BB thread, where people were asking why 
the systematic absences get scrubbed out of the mtz files at all.  I 
must agree that I do not understand the rationale either:  the symmetry 
should be simply a label attached to the reflections, not something that 
wipes out potential observations.


(I'd be very happy to be wrong about this.)

Frank





On 06/04/2018 01:01, James Holton wrote:


I say "putative" because I don't know what your space group is.

In P212121 the reflection h,k,l = 0,0,1 is absent, but in P222 it is 
not absent.  So, if your unit cell is a=30 b=40 c=60 the lowest-angle 
hkl you will get is at 60 A resolution (0,0,1) in P222, but the 
lowest-angle reflection you will get out of P212121 will be (0,1,1), 
at 33.3 A resolution.  This is because 0,1,0 is also absent.  So, if 
you ever specify P212121 in your pipeline the 0,0,1 reflection will be 
lost.  Same thing happens with most any screw-vs-rotation axis 
assignment.


You loose other reflections to absences too, of course, but the 
lowest-order ones have an annoying habit of defining the "resolution 
range", and this can sometimes get set at one point in the pipeline 
and applied to subsequent operations, even if you change the space 
group back.  This could also be happening to you?


It is also possible to a subtle change in unit cell can move your 
lowest-order (and also the highest order) reflections across the 
defined "resolution range" boundaries.  Sometimes even round-off error 
can be enough.


So, if low-resolution is important it is always a good idea to replace 
the low-angle resolution limit with  A.  Just be sure your 
beamstop was properly masked off.


-James Holton
MAD Scientist


On 4/5/2018 10:55 AM, Pearce, N.M. (Nick) wrote:
Could you expand a bit on what you mean by a “putative” systematic 
absence? (e.g. why only the lowest order hkl?)




On 5 Apr 2018, at 19:39, James Holton <jmhol...@slac.stanford.edu 
<mailto:jmhol...@slac.stanford.edu>> wrote:


You need to be careful with the exact space group at the particular 
stage in your pipeline here.  Often the lowest-order hkl is a 
putative systematic absence, so if you uniqueify in P222 you will 
get it, but if you uniqueify in P212121, then you won't.  That sort 
of thing.  Note that it doesn't matter what the "true" space group 
is, it only matters what is in the mtz header when you run uniqueify.


Could that be what is going on?

-James Holton

MAD Scisntist


On 4/5/2018 3:52 AM, Frank von Delft wrote:


Hello - can anybody shed light on this mystery:

We need (for PanDDA analysis) a lot of datasets each to have the 
complete set of low resolution indices, whether measured or not. 
(Refmac adds the estimates as DFc, which is crucial when comparing 
maps.)


In ccp4, there are two obvious ways to get these indices complete:

  * uniqueify
  * CAD using the keyword "RESOLUTION FILE 1 999 "  (999
is the low resolution limit).

Mystifyingly, in ~1% of datasets, one or the other route misses one 
or two indices.  Our work-around is to go belt-and-braces and run 
both for each dataset.



It does however remain a bug.  Does anybody have any idea what's 
happening?  We can send example datasets to any volunteers who want 
to fiddle with it.


phx

Re: [ccp4bb] (arcane) How to generate complete set of indices at low res

[Frank von Delft]

No, the point is:  uniqueify manages to not /alw//ays/ do this.

I suppose I'm really asking:  who wants an example file to debug it?  
Because we have failed utterly.


Frank


On 05/04/2018 12:04, Eleanor Dodson wrote:

You need to be a bit more specific! - unbiqueify is meant to do this..
I didnt know CAD would generate indices not in the input file, unless 
you asked to generate a full set of FreeR terms, when the job I 
thought ran uniqueify?

Eleanor

On 5 April 2018 at 11:52, Frank von Delft <frank.vonde...@sgc.ox.ac.uk 
<mailto:frank.vonde...@sgc.ox.ac.uk>> wrote:


Hello - can anybody shed light on this mystery:

We need (for PanDDA analysis) a lot of datasets each to have the
complete set of low resolution indices, whether measured or not. 
(Refmac adds the estimates as DFc, which is crucial when comparing
maps.)

In ccp4, there are two obvious ways to get these indices complete:

  * uniqueify
  * CAD using the keyword "RESOLUTION FILE 1 999 "  (999
is the low resolution limit).

Mystifyingly, in ~1% of datasets, one or the other route misses
one or two indices.  Our work-around is to go belt-and-braces and
run both for each dataset.


It does however remain a bug.  Does anybody have any idea what's
happening?  We can send example datasets to any volunteers who
want to fiddle with it.

phx

[ccp4bb] (arcane) How to generate complete set of indices at low res

[Frank von Delft]

Hello - can anybody shed light on this mystery:

We need (for PanDDA analysis) a lot of datasets each to have the 
complete set of low resolution indices, whether measured or not. (Refmac 
adds the estimates as DFc, which is crucial when comparing maps.)


In ccp4, there are two obvious ways to get these indices complete:

 * uniqueify
 * CAD using the keyword "RESOLUTION FILE 1 999 " (999 is the
   low resolution limit).

Mystifyingly, in ~1% of datasets, one or the other route misses one or 
two indices.  Our work-around is to go belt-and-braces and run both for 
each dataset.



It does however remain a bug.  Does anybody have any idea what's 
happening?  We can send example datasets to any volunteers who want to 
fiddle with it.


phx

Re: [ccp4bb] Anderson?Evans polyoxotungstate (TEW)

[Frank von Delft]

We bought some recently hoping for some magic for a specific project 
that we needed new crystal forms for.  Alas, no fairy dust magic in our 
hands.  Maybe we didn't do the protocol right - but of course, one 
doesn't expect to have to do that with fairy dust. We haven't tried with 
many things, though.


All these tricks published over the years seem to /on average/ but 
hardly ever when you need them.  Which is fine if you're funded to 
generate lots of structures, but frustrating if you're funded to crack 
specific science.


While I'm at it:  for those of you asked to review such methods in the 
future, could you insist on them being tested on a lot more than 
lysozyme and thaumatin?


phx


On 31/03/2018 01:44, Whitley, Matthew J. wrote:
I would also be interested in learning whether polyoxotungstate has 
worked wonders for anyone.  At the current price of 387 EUR/gram, it 
is a bit too expensive for us to seriously consider giving it a try.  
Yes, a gram is a lot of compound and would probably last a long time, 
but there are other things at present that we know would give us more 
bang for our buck euro.  If anyone has any great stories of how it was 
a game changer for them, that would do a lot to motivate us to give it 
a try.  Eager to hear about your experiences using the compound.


Thanks,
Matthew
---
Matthew J. Whitley, Ph.D.
Research Instructor
W. Furey Lab
Department of Pharmacology & Chemical Biology
University of Pittsburgh School of Medicine
On 3/30/2018 7:00 PM, CCP4BB automatic digest system wrote:

--
Date:Fri, 30 Mar 2018 20:24:29 +0200
From:Nikolay Dobrev
Subject: Anderson?Evans polyoxotungstate (TEW)

Dear all,
I apologize for my off-topic question.
I want to ask if anyone has so far used the Anderson-Evans
polyoxotungstate
(https://na01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.jenabioscience.com%2Fcrystallography-cryo-em%2Fscreening%2Fxp-screen%2Fx-tew-anderson-evans-polyoxotungstate=01%7C01%7Cmjw100%40PITT.EDU%7C27d0177bd91c4d421ed508d59692ef9d%7C9ef9f489e0a04eeb87cc3a526112fd0d%7C1=IXVk9RvttYWokRiY2M9H43br5JHo2REjfx9HBML13rI%3D=0).
Did someone see an improvement in crystal quality/diffraction?
Any comments will be highly appreciated.

Nikolay Dobrev



Nikolay Dobrev
PhD Student in AG Sinning & AG Fischer
Biochemie Zentrum
Heidelberg University
Im Neuenheimer Feld 328
69120 Heidelberg
Germany
Phone: +49 6221 54 4796
Email: 

[ccp4bb] Deadline: XChem fragment screening at Diamond (and iNEXT) - WEDS 4th APRIL 5pm

[Frank von Delft]

Dear Protein Crystallographers and Drug Discoverers

A reminder that we are again inviting proposals for performing 
crystal-based fragment screening at Diamond's XChem facility at beamline 
I04-1, for the next allocation period (October 2018 to March 2019).


   *The deadline for proposals is WEDNESDAY 4TH APRIL @ 5PM.*

   *Details of how to submit at this page
   
<http://www.diamond.ac.uk/Beamlines/Mx/Fragment-Screening/Applying-for-Fragment-Screening.html>.

   *

Full details of the facility are available here 
<http://www.diamond.ac.uk/Beamlines/Mx/Fragment-Screening.html>.  It 
supports the full crystal-to-structure experiment, and since opening for 
users in 2015, it has hosted over 60 users from academia and industry 
(>70k crystals), consistently yielding credible, high quality fragment 
hits.  With the right crystals, it'll keep you busy for less than a few 
weeks; and you get lots of support and advice.


The calls are heavily oversubscribed, so please pay close attention to 
the instructions and guidelines.


Access for EU users is funded via iNEXT <http://www.inext-eu.org/> (but 
only if you follow the instructions!);  however we welcome all 
international proposals.




--
Prof Frank von Delft
Associate Professor

Principal Beamline Scientist: I04-1
Diamond Light Source
+44 1235 778997

Principal Investigator: Protein Crystallography
Structural Genomics Consortium
Oxford University
+44 1865 617583

Visiting Professor
Department of Biochemistry
University of Johannesburg
South Africa

[ccp4bb] XChem user progamme: recruiting staff

[Frank von Delft]

Dear MXers

We are recruiting two scientists to Diamond's XChem facility 
<http://www.diamond.ac.uk/Beamlines/Mx/Fragment-Screening.html> to 
expand its user programme for crystallographic fragment screening.


The facility, set up at beamline I04-1 in partnership with the 
SGC-Oxford, is now routinely hosting users every week, allowing them to 
find convincing fragment hits with a few days' worth of experiments.  In 
2017, over 30 users measured over 35,000 crystals in academic and 
industrial XChem experiments.


Demand has been steadily increasing, and along with expanding the lab 
facilities and available beamtime, we are setting up a dedicated team 
that will be responsible for streamlining academic and industrial 
access, and developing the methods to extend the experiment's scope and 
ensure the programme is robust in the longer term.


Recruitment details are here 
<http://www.diamond.ac.uk/Careers/Vacancies/All/016_18_CH.html> and here 
<http://www.diamond.ac.uk/Careers/Vacancies/All/006_18_TH.html> 
(advertised separately for admin reasons).



--
Prof Frank von Delft

Principal Beamline Scientist: I04-1
Diamond Light Source
+44 1235 778997 (office: M,T,T)
+44 7471 026103 (mobile)

Principal Investigator: Protein Crystallography
Structural Genomics Consortium
Oxford University
+44 1865 617583 (office: W,F)

[ccp4bb] XChem compound design: recruiting programmer / software engineer

[Frank von Delft]

Dear MXers

We are recruiting a software engineer (or scientific programmer, or 
geek-minded scientist, or scientifically-minded geek) to help us get a 
lot better at designing compounds from hits from crystallographic 
fragment screening.


The post is linked to the XChem facility 
<http://www.diamond.ac.uk/Beamlines/Mx/Fragment-Screening.html> at 
Diamond's beamline I04-1, set up in partnership with the SGC-Oxford, 
which is now routinely hosting users every week, allowing them to find 
convincing fragment hits with a few days' worth of experiments.  In 
2017, over 30 users measured over 35,000 crystals in academic and 
industrial XChem experiments.


To confront the next bottleneck, namely converting low potency fragments 
into high-potency compounds, we are setting up a suite of easily 
accessible computational tools that streamline the obvious yet 
surprisingly fiddly analyses by which to identify the most sensible 
follow-up compounds that are easy to make or procure.


The (initially) two-year post will, in a team of three and depending on 
interests, build infrastructure, harden existing algorithms or help 
evolve new ones, do web interface design, or any combination of the above.


The project is seeding a nascent effort, for now aspirationally 
code-named CCP-CMC (/CompMedChem/, http://www.ccp-cmc.org/), to bring 
the awesome collaborative ethos of CCP4 and other MX tools to 
computational medicinal chemistry.


Recruitment details are here 
<https://www.recruit.ox.ac.uk/pls/hrisliverecruit/erq_jobspec_version_4.display_form?p_company=10_internal_external=E_display_in_irish=N_process_type=_applicant_no=_form_profile_detail=_display_apply_ind=Y_refresh_search=Y_recruitment_id=132678>.  
Deadline is Monday 29 Jan (it's wrong in the link).





--
Prof Frank von Delft

Principal Beamline Scientist: I04-1
Diamond Light Source
+44 1235 778997 (office: M,T,T)
+44 7471 026103 (mobile)

Principal Investigator: Protein Crystallography
Structural Genomics Consortium
Oxford University
+44 1865 617583 (office: W,F)

[ccp4bb] Deadline reminder: XChem fragment screening at Diamond (and iNEXT) - SUNDAY 1st OCTOBER

[Frank von Delft]

Dear Protein Crystallographers and Drug Discoverers

A reminder that we are again inviting proposals for performing 
crystal-based fragment screening at Diamond's XChem facility at beamline 
I04-1, for the next allocation period (April 2018 to Sept 2018).


   *The deadline for proposals is NEXT SUNDAY 1st OCTOBER 5PM.*

   *Details of how to submit at this page
   
<http://www.diamond.ac.uk/Beamlines/Mx/Fragment-Screening/Applying-for-Fragment-Screening.html>.

   *

Full details of the facility are available here 
<http://www.diamond.ac.uk/Beamlines/Mx/Fragment-Screening.html>.  It 
supports the full crystal-to-structure experiment, and since opening for 
users in 2015, it has hosted over 50 users from academia and industry, 
with over 65 experiments (>50k crystals) consistently yielding credible, 
high quality fragment hits.  With the right crystals, it'll keep you 
busy for less than a few weeks; and you get lots of support and advice.


The calls are heavily oversubscribed, so please pay close attention to 
the instructions and guidelines.


Access for EU users is funded via iNEXT <http://www.inext-eu.org/> (but 
only if you follow the instructions!);  however we welcome all 
international proposals.




--
Prof Frank von Delft
Associate Professor

Principal Beamline Scientist: I04-1
Diamond Light Source
+44 1235 778997

Principal Investigator: Protein Crystallography
Structural Genomics Consortium
Oxford University
+44 1865 617583

Visiting Professor
Department of Biochemistry
University of Johannesburg
South Africa

Re: [ccp4bb] "reset" a structure before re-refinement

[Frank von Delft]

On the same question, asked some time ago, Eleanor (or James?) pointed 
out that the this perturbation changes the phases only of the higher 
resolution reflections.


I believe the implied conclusion was that "resetting" a structure does 
not have the same effect on all phases as randomising them all a bit 
explicitly -- which is what people seem to think they want but would 
produce garbage structures (or garbage maps), and ones that can't be 
quickly fixed by a simple round of refinement.


That last bit is my interpretation;  has anybody tested this?

phx


On 18/08/2017 07:51, Graeme Winter wrote:

Dear all,

Many thanks for all of your suggestions - it seems that I was looking with the 
wrong search terms (perturb => shake) and there are indeed many tools out there 
for performing this.

Problem solved :-)

Best wishes Graeme


On 17 Aug 2017, at 18:18, Victor Lamzin  wrote:

Dear Graeme,
You can also type the following on a command line, optional commands are given 
in square parentheses.
Victor

$warpbin/arp_warp
mode shakemodel allatoms
files ccp4 xyzin FILENAME.pdb xyzout FILENAME.pdb
symmetry SPACEGROUP
shakemodel   [ bexclude B1 ] [ breset B1 B2 ] [ randomise X ] [ shift X Y Z ]
end


On 17/08/2017 17:17, Graeme Winter wrote:

Dear All,

Is there a protocol out there to gently perturb atomic positions so that re-running 
refinement can essentially put them back without bias from the original refinement? In 
particular, if trying to perform the Karplus and Diederichs paired refinement protocol, I 
do not want to run the lower resolution refinements with the "memory" of the 
weak high resolution data present... and only have the refined structure to work from...

Am using refmac5, but any pdb randomizer would hit the spot

Many thanks Graeme

Re: [ccp4bb] crystallization optimization

[Frank von Delft]

Yes, exactly.  Thanks for doing the Right Thing and posting the actual 
diagram.



On 12/07/2017 16:26, Patrick Shaw Stewart wrote:


Alun

I agree Frank's point is very interesting - and he intriguingly refers 
us to the phase diagram.


Is the point that Line A is longer than Line B ?

Best wishes

Patrick











On 12 July 2017 at 14:40, Alun R Coker <alun.co...@ucl.ac.uk 
<mailto:alun.co...@ucl.ac.uk>> wrote:


Hi Everyone,

Franks point is really interesting. We routinely reduce the
protein concentration when we see too many precipitated wells, but
we never dilute the screen. Has anyone tried this?

All the best,

Alun


On 12/07/17 08:48, Frank von Delft wrote:


The point I was failing to make:  reducing either protein or
precipitant concentration will indeed reduce nucleation, but
often won't get you bigger or more single crystals:  it will just
make the appearance of crystals less reliable.

The way to get big single reliable crystals is to /increase/
protein and /greatly/ reduce precipitant.

(Even better:  do seeding.  Like Vicky said. Incredible how often
people don't bother to do seeding, yet it solves so many problems.)

phx


On 12/07/2017 07:50, Vicky Tsirkone wrote:

Dear Frank,

I may see in the attached pic several nucleation points and a
considerable amount of microcrystals. Based to my knowledge
decreasing the concentration of the precipitant and/or the
protein concentration would be a reasonable approach to refine
the initial hits.
By checking the diagram as you correctly mentioned you may see
that the fine tuning of protein and precipitant concetration may
lead to the desirable result without reaching the precipitation
zone.

Patrick just check your screens. Just a rule of thumb, if you
see precipitation in the ~60% of your drops then you should
definitely reduce the protein concentration.

ps dont forget to try the *streak seeding*, as well.

Have a nice day and again good luck.

Vicky

On Wed, Jul 12, 2017 at 8:50 AM, Frank von Delft
<frank.vonde...@sgc.ox.ac.uk
<mailto:frank.vonde...@sgc.ox.ac.uk>> wrote:

Actually, you should try /increasing/ the protein
concentration - a lot.  But be prepared to drop the
precipitant concentration to almost nothing (1 or 2% isn't
"low").

To understand why, look at the phase diagram and what we
assume about vapour diffusion.  (Which I'm assuming is what
you're doing.)


On 12/07/2017 06:28, Vicky Tsirkone wrote:

Dear Patrick,

You may reduce the protein concentation, as well.
Another option could be the *streak seeding* by exploiting
the drop of your initial condition.

Good luck,

V.T.

On Mon, Jul 10, 2017 at 7:17 PM, Patrick Shaw Stewart
<patr...@douglas.co.uk <mailto:patr...@douglas.co.uk>> wrote:


Microseed them into two or three random screens.

Search for MMS and rMMS online.

Good luck

Patrick




On 10 July 2017 at 15:47, Liuqing Chen
<519198...@163.com <mailto:519198...@163.com>> wrote:

hello everyone!
I get a condition (10% w/v PEG 6000, 100mm HEPES
PH7.0) in which my protein grow small  needle like
crystals, how can i optimize it to get bigger
crystals?  the attach is the crystals  figure.
thanks in advance
sincerely
Liuqing Chen




-- 
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

http://www.douglas.co.uk
 Tel: 44 (0) 148-864-9090 <tel:01488%20649090> US
toll-free 1-877-225-2034 <tel:%28877%29%20225-2034>
 Regd. England 2177994, VAT Reg. GB 480 7371 36









-- 
Dr Alun R. Coker

Senior Lecturer
Wolfson Institute for Biomedical Research
University College London
The Cruciform Building
London
WC1E 6BT

Tel:020 7679 6703 Ext 46703 <tel:020%207679%206703>
Web:www.ucl.ac.uk/pxmed <http://www.ucl.ac.uk/pxmed>




--
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

http://www.douglas.co.uk
 Tel: 44 (0) 148-864-9090 <tel:01488%20649090>US toll-free 
1-877-225-2034

 Regd. England 2177994, VAT Reg. GB 480 7371 36