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. 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