I'd like to append a very important caveat to this discussion: most of the talk on Rfree as protection against overfitting is perfectly correct, if your dataset is high enough resolution. Remember that Rfree only provides protection against one form of overfitting: that is, fitting of atoms into random noise. What it doesn't protect well against is fitting the wrong atoms into real density. Remember, all your x-ray data ultimately says is "there are electrons here" - your R-factors don't care where those electrons come from, as long as they're present in about the right numbers (with some fudge-room for B-factors and occupancies). If you browse through the back catalogue of >3A models, you'll find some with horrendous geometry statistics but remarkably good R-factors (both work and free) - ultimately, I think, because the model atoms have been "overstuffed" into density that is real according to both the working and free data. In quite a few such cases I find that even after extensive reworking I'm unable to beat the original R-free, despite every other metric improving markedly.
Best regards, Tristan ________________________________ From: CCP4 bulletin board <CCP4BB@JISCMAIL.AC.UK> on behalf of Barone, Matthias <bar...@fmp-berlin.de> Sent: 20 October 2020 12:59 To: CCP4BB@JISCMAIL.AC.UK <CCP4BB@JISCMAIL.AC.UK> Subject: Re: [ccp4bb] AW: [ccp4bb] over-fitting? over-refinement? Eleanor rises a very important practical point here..."sidechains at the solvent interface have multiple conformations, and that as a result the water networks should also have partial occupancies". I was fighting with such a model for half a year and also tested XSHEL (there was a thread in here for that..). Coupling partial occupancies of sidchains with waters and other sidchains is a horrendously time-consuming task...and in the end, as Eleanor said, "correcting these details does not change the Rfactors at all". You just get fed up with that puzzle and stop right there. best, matthias Dr. Matthias Barone AG Kuehne, Rational Drug Design Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) Robert-Rössle-Strasse 10 13125 Berlin Germany Phone: +49 (0)30 94793-284 ________________________________ From: CCP4 bulletin board <CCP4BB@JISCMAIL.AC.UK> on behalf of Eleanor Dodson <0000176a9d5ebad7-dmarc-requ...@jiscmail.ac.uk> Sent: Tuesday, October 20, 2020 12:40:19 PM To: CCP4BB@JISCMAIL.AC.UK Subject: Re: [ccp4bb] AW: [ccp4bb] over-fitting? over-refinement? It is always hard to know when to stop tweaking a model.. We know from high resolution studies that many sidechains at the solvent interface have multiple conformations, and that as a result the water networks should also have partial occupancies. But usually correcting these details does not change the Rfactors at all - nor contribute much to the biological relevance of your structure! So often the point to stop is when you get fed up, Phil Evans said years ago - I spend 95% of my time on 5% of the structure, most of which is unimportant.. In practice I let the difference maps decide when to stop - 10 Sigma peak - think why - lots of 5 Sigma positive and negative ones not so important Eleanor On Tue, 20 Oct 2020 at 11:27, Schreuder, Herman /DE <herman.schreu...@sanofi.com<mailto:herman.schreu...@sanofi.com>> wrote: A practice that was very popular before the Rfree came around was to fit a water molecule in every noise peak. One would get spectacular low Rfactors this way, but I cannot imagine that anyone would believe that this would be fitting and not over-fitting. Best, Herman Von: CCP4 bulletin board <CCP4BB@JISCMAIL.AC.UK<mailto:CCP4BB@JISCMAIL.AC.UK>> Im Auftrag von Sam Tang Gesendet: Dienstag, 20. Oktober 2020 05:27 An: CCP4BB@JISCMAIL.AC.UK<mailto:CCP4BB@JISCMAIL.AC.UK> Betreff: [ccp4bb] over-fitting? over-refinement? Hi, the question may be a bit weird, but how do you define 'over-fitting' in the context of structure refinement? From users' perspective the practical aspect is to 'fit' the model into the density. So there comes this question from our juniors: fit is fit, how is a model over-fit? BRS Sam ________________________________ 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://eur01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.jiscmail.ac.uk%2Fcgi-bin%2FWA-JISC.exe%3FSUBED1%3DCCP4BB%26A%3D1&data=04%7C01%7CHerman.Schreuder%40SANOFI.COM%7Cfca18f01417745b3655008d874a81d74%7Caca3c8d6aa714e1aa10e03572fc58c0b%7C0%7C0%7C637387612965782189%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C1000&sdata=s1FpY1ufI7De3N6J2%2FivUy4zehp%2BcGl1gGjHeNrzUeA%3D&reserved=0> ________________________________ 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 ######################################################################## 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/
