Hi River, What's in a name? That which we call a predicted structure By any other name would still be uncertain until validated experimentally
Cheers, Quyen > On Apr 3, 2023, at 2:12 PM, Xiao, Chuan <[email protected]> wrote: > > You raised a very good question: why we are asking this question now? Maybe > the answer is somewhere on the fact that Alphafold is a “revolution” in the > prediction field (borrow the term from resolution revolution in cryo-EM). > > Anyway, when reading all these discussions, it made me think how I came to US > to learn how to solve a structure. My Master training is more like > bioinformatics. My second paper has a component of structural homology > modeling after sequencing some Rice genes. The paper was rejected by the > reviewers asking how I could proof my structural modeling (prediction) was > correct. At that time, I decided to learn how to solve the structure to proof > my prediction is correct. Now, it is interesting to see now the question is > on the other side. 😊 > > River > > From: CCP4 bulletin board <[email protected] > <mailto:[email protected]>> On Behalf Of Quyen Hoang > Sent: Sunday, April 2, 2023 10:20 AM > To: [email protected] <mailto:[email protected]> > Subject: Re: [ccp4bb] [External] Re: [ccp4bb] Structure prediction - waiting > to happen > > EXTERNAL EMAIL: This e-mail is from a sender outside of the UTEP system. Do > not click any links or open any attachments unless you trust the sender and > know the content is safe. > Please forward suspicious emails to [email protected] > <mailto:[email protected]> or call 915.747.6324 > > Thank you for having this conversion. > I have heard this question more than once (why is experimental determination > needed when there is Alphafold) at grant study sections. Some came from > structural biologists, so hopefully, the discussion here would help them > also. > Computational modeling had existed for decades before Alphafold, and no one > ever questioned then, as far as I am aware, the need for experimental > determination of the modeled structures regardless of how accurate the > predicted models may have been (for example an MD state of a point mutation > using a high-resolution X-ray model as a starting model), so I am confused as > to why we are asking this question now. In my view, predicted model, as good > as it may be, is still a prediction. > > Cheers, > Quyen > > Quyen Hoang, PhD > Associate Professor > Department of Biochemistry and Molecular Biology > Adjunct Associate Professor of Neurology > Principal Investigator of the Stark Neurosciences Research Institute > Indiana University School of Medicine > 635 Barnhill Drive > Medical Sciences Building, room MS0013C > Indianapolis, IN 46202 > 317-274-4371 <tel:317-274-4371> > > > > On Apr 2, 2023, at 10:52 AM, Eugene Valkov <[email protected] > <mailto:[email protected]>> wrote: > > > It depends on the problem under investigation. For example, if you propose to > perform drug discovery with membrane proteins in a lipid/detergent > environment or study the structural organization of large ribonucleoprotein > assemblies, then AlphaFold will be of limited value and you should point this > out in the rebuttal. > > If one of your aims is to study a protein, divide it into pieces, and solve > structures of domains, then this is justifiably questioned by reviewers in > light of the information provided by structure prediction. Perhaps in the > reviewer's opinion, there is no need to use substantial funds and time to > solve that structure. A more competitive proposal may then re-focus on > requesting resources for using the structural hypotheses to probe the > mechanism with more ambitious experimental structural aims or to take a > deeper dive into the function. > > As Darwin said, it is not the strongest or the fastest (or even the most > intellectual!) that survives. > > On Sun, 2 Apr 2023 at 11:28, Srivastava, Dhiraj <[email protected] > <mailto:[email protected]>> wrote: > That’s the point. All these predictions can not replace experiments and they > should be used only in the absence of experimental structures, that too with > caution. A biophysicist and structural biologist understand this but most of > the non-experts (including the reviewers of the grants from non-structural > biology study sections) don’t understand this and think that with alphafold, > there is no need for experimentally determined structures. That’s more > damaging than helpful. > > > From: CCP4 bulletin board <[email protected] > <mailto:[email protected]>> on behalf of Eugene Valkov > <[email protected] <mailto:[email protected]>> > Sent: Sunday, April 2, 2023 10:10 AM > To: [email protected] <mailto:[email protected]> > <[email protected] <mailto:[email protected]>> > Subject: Re: [ccp4bb] [External] Re: [ccp4bb] Structure prediction - waiting > to happen > > Predicted structures lack the precision and accuracy of > experimentally-determined structures at high resolution with all the benefits > of unbiased co-discovery of solvent molecules, ions, ligands, etc., bound to > molecules of interest. > > It is also true that AI-assisted structure prediction can be stunningly > accurate to the level of correctly identifying interfacing residues between > interacting proteins and accurately recapitulating the architectures of > large, multi-domain complexes. AI-assisted structure prediction is immensely > liberating in lowering the threshold to generate testable hypotheses for > those lacking access to experimental structural biology resources. > > AlphaFold and related structure prediction tools are here to stay, and no > magic incantations in funding proposals will likely make them disappear. So > rather than wring our hands as a community and mourning the loss of > ‘divide-and-conquer’ structural biology, which was a rich vein to mine over > the last decades, we should adapt to structure prediction and normalize its > use, with proper controls and caveats, as part of our arsenal of tools and > methods to focus on the questions under investigation. > > With best wishes, > Eugene > > Eugene Valkov, D.Phil. > Stadtman Investigator > RNA Biology Laboratory > Center for Cancer Research > National Cancer Institute > Frederick MD 21702, USA > (301) 846-1823 > > > On Sun, 2 Apr 2023 at 10:44, jacinto.ls <http://jacinto.ls/> > <[email protected] <mailto:[email protected]>> wrote: > I am also not sure whether AlphaFold can address the impact of ions and other > cofactors on the fold of many proteins. > > Best wishes, > Jacinto > On 2/4/23 16:20, Srivastava, Dhiraj wrote: > > May be this article is of some help suggesting the need of experimental > structures despite excellent alphafold model. > https://www.nature.com/articles/s41401-022-00938-y > <https://www.nature.com/articles/s41401-022-00938-y> > > From: CCP4 bulletin board <[email protected]> > <mailto:[email protected]> on behalf of Ian Tickle <[email protected]> > <mailto:[email protected]> > Sent: Sunday, April 2, 2023 8:28 AM > To: [email protected] <mailto:[email protected]> > <[email protected]> <mailto:[email protected]> > Subject: [External] Re: [ccp4bb] Structure prediction - waiting to happen > > > All, the first hurdle will of course be whether the AlphaFold model works as > a MR model, even with the 100% completeness and sequence identity of a > bespoke model. The question is what B factors to use or which disordered > bits to leave out, as that can strongly influence the result (perhaps use > info from a similar structure). If it doesn't work in MR that's a pretty > good indication that it's too far from reality to be useful for looking at > detailed interactions. > > Does anyone know of a systematic investigation of the success rate of > AlphaFold models in MR ? That would be useful ammunition ! > > Cheers > > -- Ian > > > On Sun, 2 Apr 2023 at 11:51, Gerard Bricogne <[email protected] > <mailto:[email protected]>> wrote: > Dear all, > > I think that quoting general viewpoints and statements, however > knowledgeable and respected their authors may be, will only exacerbate the > climate of clashing prejudices between two camps and is bound to sustain a > war of opinions rather than lead to a rational acceptance that something has > changed. The frustration is that one camp (the AlphaFold believers) can be > viewed as in effect preventing experiments that could prove it wrong. > > One way to deal with this obstruction would be to provide, in each > particular case, evidence that the AlphaFold results "do not cut it" as the > sole provider of 3D information within the project at hand. This means that > every grant proposal requesting resources towards a crystallographic > structure solution should document the fact that AlphaFold predictions have > been performed (or, often, looked up in a database of pre-cooked results) > but do not provide the accuracy required for the proposed investigation. If > this step of writing up the "Background" section of the grant actually > delivers a useful result, then everyone will be happy; and if it doesn't, > then the case for the need to allocate resources to solving the structure by > crystallography will be unassailable. In this way, AlphaFold will be a game > changer (we have known that since July 2021) but not a game killer. Savvas > alluded to a similar approach, but it could be made a formal requirement > acceptable to both proposers and reviewers, who would then both be dealing > with the situation in a scientific rather than dogmatic manner. > > > With best wishes, > > Gerard. > > -- > On Sat, Apr 01, 2023 at 06:54:33PM +0000, Goldman, Adrian wrote: > > I think this is all true - and I’ve been putting things like this into my > > (failing) grants - but I get the dispiriting sense that the medics think > > (to borrow a line from hamlet) “the applicant doth protest too much > > methinks”. > > > > Well if as per James H today ;), we deposit coordinates to 1sf, alphafold > > will be just fine. > > > > Of course the coordinates won’t be of any use to anybody, but the pictures > > will be nice. > > > > Adrian > > > > Sent from my iPhone > > > > > On 1 Apr 2023, at 21:39, Randy John Read <[email protected] > > > <mailto:[email protected]>> wrote: > > > > > > There’s also this preprint with Tom Terwilliger as lead author: > > > https://www.biorxiv.org/content/10.1101/2022.11.21.517405v1 > > > <https://www.biorxiv.org/content/10.1101/2022.11.21.517405v1>. The title > > > is “AlphaFold predictions: great hypotheses but no match for experiment”. > > > > > > Best wishes, > > > > > > Randy > > > > > >> On 1 Apr 2023, at 18:18, Savvas Savvides > > >> <[email protected] > > >> <mailto:[email protected]>> wrote: > > >> > > >> Dear Rams, > > >> > > >> I salute you for sharing this. > > >> > > >> Just a week ago, I also received a remark along these lines on a > > >> declined grant application. The remark was the only unfavourable point, > > >> which suggested that it must have weighed disproportionally towards the > > >> negative outcome. This was a two-stage evaluation process and the grant > > >> was cut in stage-1 where it was evaluated by a small group of > > >> evaluators, none of whom was a structural biologist/biochemist. Stage-2 > > >> would have involved peer review by international experts. > > >> > > >> Despite my initial disbelief about what this remark might have caused > > >> and upon reflection, I realized that it might be time to become > > >> proactive in future applications in anticipation of the apparent growing > > >> trend towards such remarks and perceptions. > > >> > > >> I think that a generalized form of preemptive text might not serve the > > >> purpose well, but perhaps well-articulated statements specific to the > > >> proposed biological problem at hand (perhaps aided by illustrations > > >> demonstrating the inability of structure prediction to address the > > >> problem at hand) might be the better way to go. Even though many of us > > >> who teach courses in experimental structural biology and structural > > >> bioinformatics at undergraduate and graduate levels are already actively > > >> addressing many of these issues, there is a much bigger and far more > > >> senior scientific population out there that makes important decisions on > > >> science policy/funding/infrastructures/evaluations/recruitment/etc that > > >> are not getting such educational exposure. > > >> > > >> The following resources provide good material and starting points to > > >> reflect and elaborate upon. > > >> > > >> The article by Perrakis and Sixma in EMBO Reports > > >> https://www.embopress.org/doi/full/10.15252/embr.202154046 > > >> <https://www.embopress.org/doi/full/10.15252/embr.202154046> > > >> > > >> The recent comment paper in Nature Methods by Thomas Jane > > >> https://doi.org/10.1038/s41592-022-01760-4 > > >> <https://doi.org/10.1038/s41592-022-01760-4> > > >> > > >> A correspondence in Science by Moore, Hendrickson, Henderson and Brunger > > >> https://www.science.org/doi/10.1126/science.abn9422?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed > > >> > > >> <https://www.science.org/doi/10.1126/science.abn9422?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed> > > >> > > >> > > >> Best wishes > > >> Savvas > > >> > > >> > > >> ---- > > >> Savvas Savvides > > >> VIB Center for Inflammation Research > > >> Ghent University, Dept. of Biochemistry & Microbiology > > >> Technologiepark 71, 9052 Ghent, Belgium > > >> > > >> Email: [email protected] <mailto:[email protected]> ; > > >> [email protected] > > >> <mailto:[email protected]> > > >> Phone: +32 (0)472 928 519 (mobile) ; +32 (0)9 331 36 60 (office) > > >> Web: https://savvideslab.sites.vib.be/en#/ > > >> <https://savvideslab.sites.vib.be/en#/> > > >> > > >>>> On 1 Apr 2023, at 16:57, Subramanian, Ramaswamy <[email protected] > > >>>> <mailto:[email protected]>> wrote: > > >>> > > >>> Ian, > > >>> > > >>> Thank you. This is not an April fools.. > > >>> Rams > > >>> [email protected] <mailto:[email protected]> > > >>> > > >>> > > >>> > > >>>> On Apr 1, 2023, at 10:46 AM, Ian Tickle <[email protected] > > >>>> <mailto:[email protected]>> wrote: > > >>>> > > >>>> ---- External Email: Use caution with attachments, links, or sharing > > >>>> data ---- > > >>>> > > >>>> > > >>>> Hi Ramaswamy > > >>>> > > >>>> I assume this is an April Fool's but it's still a serious question > > >>>> because many reviewers who are not crystallographers or electron > > >>>> microscopists may not fully appreciate the difference currently > > >>>> between the precision of structures obtained by experimental and > > >>>> predictive methods, though the latter are certainly catching up. The > > >>>> answer of course lies in the mean co-ordinate precision, related to > > >>>> the map resolution. > > >>>> > > >>>> Quoting https://people.cryst.bbk.ac.uk/~ubcg05m/precgrant.html > > >>>> <https://people.cryst.bbk.ac.uk/~ubcg05m/precgrant.html> : > > >>>> > > >>>> "The accuracy and precision required of an experimentally determined > > >>>> model of a macromolecule depends on the biological questions being > > >>>> asked of the structure. Questions involving the overall fold of a > > >>>> protein, or its topological similarity to other proteins, can be > > >>>> answered by structures of fairly low precision such as those obtained > > >>>> from very low resolution X-ray crystal diffraction data [or > > >>>> AlphaFold]. Questions involving reaction mechanisms require much > > >>>> greater accuracy and precision as obtained from well-refined, > > >>>> high-resolution X-ray structures, including proper statistical > > >>>> analyses of the standard uncertainties (s.u.'s) of atomic positions > > >>>> and bond lengths.". > > >>>> > > >>>> According to https://www.nature.com/articles/s41586-021-03819-2 > > >>>> <https://www.nature.com/articles/s41586-021-03819-2> : > > >>>> > > >>>> The accuracy of AlphaFold structures at the time of writing (2021) was > > >>>> around 1.0 Ang. RMSD for main-chain and 1.5 Ang. RMSD for side-chain > > >>>> atoms and probably hasn't changed much since. This is described as > > >>>> "highly accurate"; however this only means that AlphaFold's accuracy > > >>>> is much higher in comparison with other prediction methods, not in > > >>>> comparison with experimental methods. Also note that AlphaFold's > > >>>> accuracy is estimated by comparison with the X-ray structure which > > >>>> remains the "gold standard"; there's no way (AFAIK) of independently > > >>>> assessing AlphaFold's accuracy or precision. > > >>>> > > >>>> Quoting https://scripts.iucr.org/cgi-bin/paper?S0907444998012645 > > >>>> <https://scripts.iucr.org/cgi-bin/paper?S0907444998012645> : > > >>>> > > >>>> "Data of 0.94 A resolution for the 237-residue protein concanavalin A > > >>>> are used in unrestrained and restrained full-matrix inversions to > > >>>> provide standard uncertainties sigma(r) for positions and sigma(l) for > > >>>> bond lengths. sigma(r) is as small as 0.01 A for atoms with low Debye > > >>>> B values but increases strongly with B." > > >>>> > > >>>> There's a yawning gap between 1.0 - 1.5 Ang. and 0.01 Ang.! Perhaps > > >>>> AlphaFold structures should be deposited using James Holton's new PDB > > >>>> format (now that is an April Fool's !). > > >>>> > > >>>> One final suggestion for a reference in your grant application: > > >>>> https://www.biorxiv.org/content/10.1101/2022.03.08.483439v2 > > >>>> <https://www.biorxiv.org/content/10.1101/2022.03.08.483439v2> . > > >>>> > > >>>> Cheers > > >>>> > > >>>> -- Ian > > >>>> > > >>>> > > >>>> On Sat, 1 Apr 2023 at 13:06, Subramanian, Ramaswamy > > >>>> <[email protected] <mailto:[email protected]>> wrote: > > >>>> Dear All, > > >>>> > > >>>> I am unsure if all other groups will get it - but I am sure this group > > >>>> will understand the frustration. > > >>>> > > >>>> My NIH grant did not get funded. A few genuine comments - they make > > >>>> excellent sense. We will fix that. > > >>>> > > >>>> One major comment is, “Structures can be predicted by alpfafold and > > >>>> other software accurately, so the effort put on the grant to get > > >>>> structures by X-ray crystallography/cryo-EM is not justified.” > > >>>> > > >>>> The problem is when a company with billions of $$s develops a method > > >>>> and blasts it everywhere - the message is so pervasive… > > >>>> > > >>>> Question: Is there a canned consensus paragraph that one can add with > > >>>> references to grants with structural biology (especially if the review > > >>>> group is not a structural biology group) to say why the most modern > > >>>> structure prediction programs are not a substitute for structural work? > > >>>> > > >>>> Thanks. > > >>>> > > >>>> > > >>>> Rams > > >>>> [email protected] <mailto:[email protected]> > > >>>> > > >>>> > > >>>> > > >>>> > > >>>> To unsubscribe from the CCP4BB list, click the following link: > > >>>> https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1 > > >>>> <https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1> > > >>>> > > >>> > > >>> > > >>> To unsubscribe from the CCP4BB list, click the following link: > > >>> https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1 > > >>> <https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1> > > >>> > > >> > > >> > > >> To unsubscribe from the CCP4BB list, click the following link: > > >> https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1 > > >> <https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1> > > >> > > > > > > ----- > > > Randy J. Read > > > Department of Haematology, University of Cambridge > > > Cambridge Institute for Medical Research Tel: +44 1223 336500 > > > The Keith Peters Building > > > Hills Road E-mail: > > > [email protected] <mailto:[email protected]> > > > Cambridge CB2 0XY, U.K. > > > www-structmed.cimr.cam.ac.uk <http://www-structmed.cimr.cam.ac.uk/> > > > > > > > > > ######################################################################## > > > > > > To unsubscribe from the CCP4BB list, click the following link: > > > https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1 > > > <https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1> > > > > > > This message was issued to members of www.jiscmail.ac.uk/CCP4BB > > > <http://www.jiscmail.ac.uk/CCP4BB>, a mailing list hosted by > > > www.jiscmail.ac.uk <http://www.jiscmail.ac.uk/>, terms & conditions are > > > available at https://www.jiscmail.ac.uk/policyandsecurity/ > > > <https://www.jiscmail.ac.uk/policyandsecurity/> > > > > ######################################################################## > > > > To unsubscribe from the CCP4BB list, click the following link: > > https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1 > > <https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1> > > > > This message was issued to members of www.jiscmail.ac.uk/CCP4BB > > <http://www.jiscmail.ac.uk/CCP4BB>, a mailing list hosted by > > www.jiscmail.ac.uk <http://www.jiscmail.ac.uk/>, terms & conditions are > > available at https://www.jiscmail.ac.uk/policyandsecurity/ > > <https://www.jiscmail.ac.uk/policyandsecurity/> > > ######################################################################## > > To unsubscribe from the CCP4BB list, click the following link: > https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1 > <https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1> > > This message was issued to members of www.jiscmail.ac.uk/CCP4BB > <http://www.jiscmail.ac.uk/CCP4BB>, a mailing list hosted by > www.jiscmail.ac.uk <http://www.jiscmail.ac.uk/>, terms & conditions are > available at https://www.jiscmail.ac.uk/policyandsecurity/ > <https://www.jiscmail.ac.uk/policyandsecurity/> > > To unsubscribe from the CCP4BB list, click the following link: > https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1 > <https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1> > > To unsubscribe from the CCP4BB list, click the following link: > https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1 > <https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1> > > > To unsubscribe from the CCP4BB list, click the following link: > https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1 > <https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1> > > To unsubscribe from the CCP4BB list, click the following link: > https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1 > <https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1> > > To unsubscribe from the CCP4BB list, click the following link: > https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1 > <https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1> > > To unsubscribe from the CCP4BB list, click the following link: > https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1 > <https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1> ######################################################################## To unsubscribe from the CCP4BB list, click the following link: https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1 This message was issued to members of www.jiscmail.ac.uk/CCP4BB, a mailing list hosted by www.jiscmail.ac.uk, terms & conditions are available at https://www.jiscmail.ac.uk/policyandsecurity/
