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 <[log in to unmask]> 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 <[log in to unmask]>
>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
>>
>>
>>
>> [log in to unmask]
>> 716-898-8623
>>
>>
>>
>>
>>
>> *From: *CCP4 bulletin board <[log in to unmask]> on behalf of Bernhard
>> Rupp <[log in to unmask]>
>> *Organization: *k.k. Hofkristallamt
>> *Reply-To: *"[log in to unmask]" <[log in to unmask]>
>> *Date: *Monday, July 22, 2019 at 1:42 PM
>> *To: *"[log in to unmask]" <[log in to unmask]>
>> *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 <
>> [log in to unmask] <mailto:[log in to unmask]>
>> <[log in to unmask]>> 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 <
>> [log in to unmask] <mailto:[log in to unmask]>
>> <[log in to unmask]>> 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 <
>>
>> >[log in to unmask] <
>> mailto:[log in to unmask]> <[log in to unmask]>>
>> 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 <
>>
>> >> [log in to unmask] <mailto:[log in to unmask]>
>> <[log in to unmask]>> 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 <
>>
>> >> >[log in to unmask] <
>> mailto:[log in to unmask]>
>> <[log in to unmask]>> 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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