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 > <00009d24f7f13e09-dmarc-requ...@jiscmail.ac.uk> 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: savvas.savvi...@ugent.be ; savvas.savvi...@irc.vib-ugent.be > 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 <subra...@purdue.edu> wrote: >> >> Ian, >> >> Thank you. This is not an April fools.. >> Rams >> subra...@purdue.edu >> >> >> >>> On Apr 1, 2023, at 10:46 AM, Ian Tickle <ianj...@gmail.com> 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 <subra...@purdue.edu> >>> 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 >>> subra...@purdue.edu >>> >>> >>> >>> >>> 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: rj...@cam.ac.uk 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/
