A recent paper in my favourite journal :-) suggests there is no correlation in crystallisation conditions even for similar proteins: http://scripts.iucr.org/cgi-bin/paper?S2053230X19000141 <http://scripts.iucr.org/cgi-bin/paper?S2053230X19000141> As you write, surface loops are likely to be different even for similar proteins and those are likely to be important for crystal contacts.
> On 23 Jul 2019, at 10:35, [email protected] > <[email protected]> wrote: > > I don't think AI will do our job in future as it heavily relies on the > crystal structures for training. However, as a community we should embrace > this technology/method to help us solve our structures. And why not start > with crystallisation? And again the PDB is in a good position here to enforce > standards which will pave the way to make use of all the information in the > database to train AI. All chemicals must be IUPAC conform an then the PDB can > decide about trivial names based on a set of rules for humans (AI doesn't > care how you name it as long as it is consistent). No longer those 20 odd > names for ammonium sulphate as Janet pointed out years ago. > > > And regarding a magic bullet (as in one size fits all), why should a kinase > crystallise in the same condition as a polymerase? They do different jobs in > a different micro-environment within the cell so their chemical properties > will be different. Perhaps there could be some common ground for evolutionary > related molecules but a conserved active site doesn't mean a similar surface > for crystal contacts which is the key bit in crystallisation, right? > > > But as Kay pointed out, crystallisation is a whole field on its own and will > go beyond the GRC and the question asked by James. > > > M > > ________________________________ > From: CCP4 bulletin board <[email protected]> on behalf of Kay Diederichs > <[email protected]> > Sent: 23 July 2019 08:59:10 > To: ccp4bb > Subject: Re: [ccp4bb] challenges in structural biology > > If you look at the nice figure at the top of the online article, do you > believe that this (or rather, the correct) arrangement of domains/ molecules > can be predicted from a couple of correlated mutations, and energy > minimization? I think AI is a long way from that. Finding the correct fold > of a compact domain, yes I think it's getting there. > > best, > Kay > > > On Tue, 23 Jul 2019 08:28:42 +0530, Nishant Varshney <[email protected]> wrote: > >> What about AI doing our job in the future? >> >> https://www.nature.com/articles/d41586-019-01357-6?utm_source=Nature+Briefing&utm_campaign=4c1d57fdf3-briefing-dy-20190722&utm_medium=email&utm_term=0_c9dfd39373-4c1d57fdf3-44201949 >> >> Best Regards >> Nishant >> >> On Mon, 22 Jul 2019 at 11:30 PM, Sarah Bowman <[email protected]> >> wrote: >> >>> I'd like to point out that the MAchine Recognition of Crystallization >>> Outcomes (MARCO) makes a start to 'deep learning applied to crystallization >>> outcomes', at least in terms of being able to classify drop images >>> efficiently. >>> >>> >>> >>> There is obviously more work to be done to correlate these data with >>> crystallization cocktail components (which Janet and Tom point out the >>> difficulties with) and positive outcomes. It seems the first step really >>> needs to be consistent descriptions and vocabulary - I fully agree with >>> Janet here! >>> >>> >>> >>> Reference on MARCO for those interested: Bruno AE, Charbonneau P, Newman >>> J, Snell EH, So DR, Vanhoucke V, et al. (2018) Classification of >>> crystallization outcomes using deep convolutional neural networks. PLoS ONE >>> 13(6): e0198883. https://doi.org/10.1371/journal.pone.0198883 >>> >>> >>> >>> Cheers, >>> >>> Sarah >>> >>> >>> >>> *Sarah EJ Bowman, PhD* >>> >>> >>> >>> Associate Research Scientist, Hauptman-Woodward Medical Research Institute >>> >>> Director, High-Throughput Crystallization Screening Center >>> >>> Research Associate Professor, Department of Biochemistry, University at >>> Buffalo >>> >>> >>> >>> Research Webpage <https://hwi.buffalo.edu/scientist-directory/sbowman/> >>> >>> www.getacrystal.org<http://www.getacrystal.org> >>> >>> >>> >>> [email protected] >>> 716-898-8623 >>> >>> >>> >>> >>> >>> *From: *CCP4 bulletin board <[email protected]> on behalf of Bernhard >>> Rupp <[email protected]> >>> *Organization: *k.k. Hofkristallamt >>> *Reply-To: *"[email protected]" <[email protected]> >>> *Date: *Monday, July 22, 2019 at 1:42 PM >>> *To: *"[email protected]" <[email protected]> >>> *Subject: *Re: challenges in structural biology >>> >>> >>> >>> What about 'deep learning' applied to crystallization outcomes? Can it >>> guide individual trials better than intuition? Can it find previously >>> unknown promising combinations on a larger scale? >>> >>> >>> >>> I think several people were well aware of this need for some sort of sound >>> machine learning already 15 years ago but we had no cloud based AI >>> >>> services then....maybe it is time to pick this up - particularly if face >>> recognition can classify the fine detail in faces maybe we finally could do >>> this with drop images as well... >>> >>> >>> >>> A summary of the state of affairs then is here: >>> >>> >>> http://www.ruppweb.org/cvs/br/rupp_2004_methods_predictive_models_crystallization.pdf >>> >>> >>> >>> LG BR >>> >>> >>> >>> >>> >>> Am 21.07.19 um 23:04 schrieb Artem Evdokimov: >>> >>> Dear Kay >>> >>> >>> >>> I disagree that 'magic bullet' is impossible. I think the definition is >>> wrong here - magic bullet to me is a rational set of methods that (when >>> executed with precision and care) enable crystallization to the maximum >>> possible benefit. This includes everything - constructs, crystallization >>> design, etc. Part of the magic bullet is also a precise knowledge when >>> crystallization is unlikely (i.e. an actual proven predictor that >>> consistently discriminates between "you're going to succeed if you work >>> hard" and "it's doomed to fail, don't bother" scenarios in crystallization. >>> >>> The above is not sexy. It does not present itself as a lovely subject on >>> which to have international cocktail parties with politicians delivering >>> fancy speeches. But that is what is needed, and no one is funding that to >>> the best of my knowledge. >>> >>> What needs to be done is a significant amount of testing, standardization, >>> and methods development from the perspective of holistic outcome (i.e. >>> crystals that work) - and none of the previously advertised 'magic bullets' >>> work the way I just described. >>> >>> Having written this, I think you're right - this is a bit of a distraction >>> from James' original point. However it's a valid opportunity for a lively >>> discussion on its own :) >>> >>> Artem >>> >>> - Cosmic Cats approve of this message >>> >>> On Sun, Jul 21, 2019 at 4:52 PM Kay Diederichs < >>> [email protected] <mailto:[email protected]> >>> <[email protected]%3e>> wrote: >>> >>> Dear Artem, >>> >>> black or white is not my way of thinking, which is why I don't >>> believe in Hannibal's approach when it comes to crystallization. >>> >>> None of the magic bullets that were advertised over the past decades >>> have proven generally applicable. I believe more in incremental >>> improvement which in this case includes a few biophysical characterization >>> methods, possibly improved microfluidics or other apparatus, and expanded >>> screens. And a lot of hard work, perseverance, intuition, frustration >>> >>> tolerance. Nothing that really needs huge funding - of course it >>> does need money, but just a share of what is anyway needed for the usual >>> lab work including expression, purification, functional characterization, >>> binding studies and the like. >>> >>> One area where a huge amount of money was burnt is crystallization in >>> space, on board of e.g. the spacelab and ISS. This is for me an example of >>> a mis-led approach to throw money at a difficult problem, with the >>> expectation of a solution. Science does not work like that, and money in >>> this case seems more to be the problem than the solution. >>> >>> This example may illustrate a certain failure of us scientists to >>> resist the temptation to promise unrealistic outcomes when confronted with >>> money provided for political reasons, which ultimately undermines our >>> credibility. But this takes us away from James' points. >>> >>> best, >>> >>> Kay >>> >>> On Sun, 21 Jul 2019 16:06:48 -0400, Artem Evdokimov < >>> [email protected] <mailto:[email protected]> >>> <[email protected]%3e>> wrote: >>> >>>> Dear Kay, >>> >>>> >>> >>>> Even the small, badly diffracting and 'messed up' crystals are still >>> >>>> crystals. There is literally a phase transition (pun very much >>> intended) >>> >>>> between growing *usable crystals* versus *having no crystals* (or >>> having >>> >>>> crystals that do not qualify as 'diffraction quality' even under the >>> most >>> >>>> favorable light). Points 2-9 fall into the 'I have crystals' bucket >>> and >>> >>>> everything else is in the 'I have no crystals' bucket. >>> >>>> >>> >>>> I am being deliberately black and white of course. >>> >>>> >>> >>>> As to whether huge funding would help to bridge the 'phase gap' - to >>> me >>> >>>> this is a purely theoretical question since to the best of my >>> knowledge >>> >>>> there never was a 'huge funding' for this particular problem :) And >>> if it >>> >>>> is true that the general belief in the art is that crystallization >>> is not >>> >>>> worth investing into because there's no hope in it then of course it >>> is a >>> >>>> self-fulfilling prophesy. >>> >>>> >>> >>>> There is an unresolved dichotomy buried in the sentiment above: it >>> seems >>> >>>> that we (the community of structural biologists) more or less >>> believe that >>> >>>> crystallization research is not fundamentally fruitful (hence the >>> >>>> no-funding situation). However, anyone who undertakes significant >>> efforts >>> >>>> to determine an actual structure using crystallography inevitably >>> *has to* >>> >>>> crystallize their target of interest - and therefore by definition >>> has hope >>> >>>> that their particular target will work out, against the overall >>> gloomy >>> >>>> outlook on the crystallization science as a whole. So we either are a >>> >>>> collective of self-induced schizophrenics, or the general sentiment >>> is >>> >>>> wrong and systematic crystallization research is meaningful and >>> >>>> fruitful - *just >>> >>>> very very hard*. >>> >>>> >>> >>>> In ~200 BC Hannibal reportedly said "I will find a way or make one". >>> I >>> >>>> think that if we approach problem #1 with this attitude (and an >>> equivalent >>> >>>> of a very large army's worth in funding) then it can be solved. >>> >>>> >>> >>>> Artem >>> >>>> >>> >>>> - Cosmic Cats approve of this message >>> >>>> >>> >>>> >>> >>>> On Sun, Jul 21, 2019 at 1:55 PM Kay Diederichs < >>> >>>> [email protected] < >>> mailto:[email protected]> <[email protected]%3e>> >>> wrote: >>> >>>> >>> >>>>> Hi Artem, >>> >>>>> >>> >>>>> you are certainly correct in that James' points 2-9 would be moot >>> if his >>> >>>>> point 1 were solved. But as long as this is not the case, we >>> resort to work >>> >>>>> with few and/or small and/or badly diffracting and/or >>> non-isomorphous >>> >>>>> crystals, which makes points 2-9 very relevant. >>> >>>>> >>> >>>>> Maybe the reason why crystallization research is not well funded >>> is that >>> >>>>> it is not expected to yield significant improvements. Personally, >>> I think >>> >>>>> that even huge funding would not result in methods that succeed in >>> >>>>> crystallizing all molecules. >>> >>>>> >>> >>>>> best, >>> >>>>> Kay >>> >>>>> >>> >>>>> On Sun, 21 Jul 2019 11:28:14 -0400, Artem Evdokimov < >>> >>>>> [email protected] <mailto:[email protected]> >>> <[email protected]%3e>> wrote: >>> >>>>> >>> >>>>>> Excellent question :) >>> >>>>>> >>> >>>>>> First of all, thank you for putting this out to the community! >>> >>>>>> >>> >>>>>> Secondly, I agree with several of us who've written that a single >>> >>>>>> conference is not enough to discuss all the possible topics. >>> >>>>>> >>> >>>>>> Thirdly, in my opinion all the other problems are secondary to >>> the main >>> >>>>>> (and only remaining!) problem in crystallography: getting >>> >>>>>> diffraction-quality protein crystals reproducibly and quickly >>> >>>>>> >>> >>>>>> The amount of funding for serious crystallization research seems >>> to be >>> >>>>>> close to non-existent. In general methodology funding is hard to >>> get, but >>> >>>>>> crystallization seems to me like the absolute underdog of the >>> method pool >>> >>>>> - >>> >>>>>> the true 'red headed stepchild' of the methods development >>> funders. >>> >>>>>> >>> >>>>>> At risk of repeating myself - the other problems (worthy, >>> significant, and >>> >>>>>> urgent as they are!) are subservient to the main issue at hand - >>> namely >>> >>>>>> that crystallization remains an unpredictable and artful >>> phenomenon while >>> >>>>>> literally all other aspects of structure determination process >>> (the gene >>> >>>>> to >>> >>>>>> structure pipeline, whatever you might call it)have made >>> astronomic leaps >>> >>>>>> forward. >>> >>>>>> >>> >>>>>> Artem >>> >>>>>> - Cosmic Cats approve of this message >>> >>>>>> >>> >>>>>> >>> >>>>>> On Mon, Jul 15, 2019 at 3:44 PM Holton, James M < >>> >>>>>> [email protected] < >>> mailto:[email protected]> >>> <[email protected]%3e>> wrote: >>> >>>>>> >>> >>>>>>> Hello folks, >>> >>>>>>> >>> >>>>>>> I have the distinct honor of chairing the next Gordon Research >>> >>>>>>> Conference on Diffraction Methods in Structural Biology (July >>> 26-31 >>> >>>>>>> 2020). This meeting will focus on the biggest challenges >>> currently >>> >>>>>>> faced by structural biologists, and I mean actual real-world >>> >>>>>>> challenges. As much as possible, these challenges will take >>> the form of >>> >>>>>>> friendly competitions with defined parameters, data, a scoring >>> system, >>> >>>>>>> and "winners", to be established along with other unpublished >>> results >>> >>>>>>> only at the meeting, as is tradition at GRCs. >>> >>>>>>> >>> >>>>>>> But what are the principle challenges in biological structure >>> >>>>>>> determination today? I of course have my own ideas, but I feel >>> like I'm >>> >>>>>>> forgetting something. Obvious choices are: >>> >>>>>>> 1) getting crystals to diffract better >>> >>>>>>> 2) building models into low-resolution maps (after failing at >>> #1) >>> >>>>>>> 3) telling if a ligand is really there or not >>> >>>>>>> 4) the phase problem (dealing with weak signal, twinning and >>> >>>>>>> pseudotranslation) >>> >>>>>>> 5) what does "resolution" really mean? >>> >>>>>>> 6) why are macromolecular R factors so much higher than >>> small-molecule >>> >>>>>>> ones? >>> >>>>>>> 7) what is the best way to process serial crystallography data? >>> >>>>>>> 8) how should one deal with non-isomorphism in multi-crystal >>> methods? >>> >>>>>>> 9) what is the "structure" of something that won't sit still? >>> >>>>>>> >>> >>>>>>> What am I missing? Is industry facing different problems than >>> >>>>>>> academics? Are there specific challenges facing electron-based >>> >>>>>>> techniques? If so, could the combined strength of all the >>> world's >>> >>>>>>> methods developers solve them? I'm interested in hearing the >>> voice of >>> >>>>>>> this community. On or off-list is fine. >>> >>>>>>> >>> >>>>>>> -James Holton >>> >>>>>>> MAD Scientist >>> >>>>>>> >>> >>>>>>> >>> >>>>>>> >>> ######################################################################## >>> >>>>>>> >>> >>>>>>> To unsubscribe from the CCP4BB list, click the following link: >>> >>>>>>> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB&A=1 >>> >>>>>>> >>> >>>>>> >>> >>>>> >>>> ######################################################################## >>> >>>>>> >>> >>>>>> To unsubscribe from the CCP4BB list, click the following link: >>> >>>>>> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB&A=1 >>> >>>>>> >>> >>>>> >>> >>>>> >>> ######################################################################## >>> >>>>> >>> >>>>> To unsubscribe from the CCP4BB list, click the following link: >>> >>>>> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB&A=1 >>> >>>>> >>> >>>> >>> >>> >>>> ######################################################################## >>> >>>> >>> >>>> To unsubscribe from the CCP4BB list, click the following link: >>> >>>> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB&A=1 >>> >>>> >>> >>> >>> >>> >>> >>> ######################################################################## >>> >>> >>> >>> To unsubscribe from the CCP4BB list, click the following link: >>> >>> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB&A=1 >>> >>> >>> >>> ######################################################################## >>> >>> >>> >>> To unsubscribe from the CCP4BB list, click the following link: >>> >>> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB&A=1 >>> >>> >>> >>> ------------------------------ >>> >>> To unsubscribe from the CCP4BB list, click the following link: >>> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB&A=1 >>> >> >> ######################################################################## >> >> To unsubscribe from the CCP4BB list, click the following link: >> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB&A=1 >> > > ######################################################################## > > To unsubscribe from the CCP4BB list, click the following link: > https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB&A=1 > > -- > This e-mail and any attachments may contain confidential, copyright and or > privileged material, and are for the use of the intended addressee only. If > you are not the intended addressee or an authorised recipient of the > addressee please notify us of receipt by returning the e-mail and do not use, > copy, retain, distribute or disclose the information in or attached to the > e-mail. > Any opinions expressed within this e-mail are those of the individual and not > necessarily of Diamond Light Source Ltd. > Diamond Light Source Ltd. cannot guarantee that this e-mail or any > attachments are free from viruses and we cannot accept liability for any > damage which you may sustain as a result of software viruses which may be > transmitted in or with the message. > Diamond Light Source Limited (company no. 4375679). Registered in England and > Wales with its registered office at Diamond House, Harwell Science and > Innovation Campus, Didcot, Oxfordshire, OX11 0DE, United Kingdom > > > ######################################################################## > > To unsubscribe from the CCP4BB list, click the following link: > https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB&A=1 ######################################################################## To unsubscribe from the CCP4BB list, click the following link: https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB&A=1
