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]> wrote: > > There’s also this preprint with Tom Terwilliger as lead author: > 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]> 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 >> >> The recent comment paper in Nature Methods by Thomas Jane >> 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 >> >> >> Best wishes >> Savvas >> >> >> ---- >> Savvas Savvides >> VIB Center for Inflammation Research >> Ghent University, Dept. of Biochemistry & Microbiology >> Technologiepark 71, 9052 Ghent, Belgium >> >> Email: [email protected] ; [email protected] >> Phone: +32 (0)472 928 519 (mobile) ; +32 (0)9 331 36 60 (office) >> Web: https://savvideslab.sites.vib.be/en#/ >> >>>> On 1 Apr 2023, at 16:57, Subramanian, Ramaswamy <[email protected]> >>>> wrote: >>> >>> Ian, >>> >>> Thank you. This is not an April fools.. >>> Rams >>> [email protected] >>> >>> >>> >>>> On Apr 1, 2023, at 10:46 AM, Ian Tickle <[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 : >>>> >>>> "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 : >>>> >>>> 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 : >>>> >>>> "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 . >>>> >>>> Cheers >>>> >>>> -- Ian >>>> >>>> >>>> On Sat, 1 Apr 2023 at 13:06, Subramanian, Ramaswamy <[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] >>>> >>>> >>>> >>>> >>>> To unsubscribe from the CCP4BB list, click the following link: >>>> 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 >>> >> >> >> To unsubscribe from the CCP4BB list, click the following link: >> 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] > Cambridge CB2 0XY, U.K. > 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 > > 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/ ######################################################################## 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/
