Re: [ccp4bb]: homology modelling?

[Gerard DVD Kleywegt <gerard@xray.bmc.uu.se>]

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since the proof of the pudding is in the eating, we ate some while evaluating
the comparative modelling bit in CASP3 (autumn 1998), using a target we had
submitted ourselves and for which we therefore had the experimental data.  at
that stage essentially all homology models performed worse than the template
(either with its own, incorrect sequence, or turned into a poly-Ala). see: T A
Jones & G J Kleywegt, Proteins, Suppl. 3, 30-46 (1999) [get a reprint via
http://xray.bmc.uu.se/cgi-bin/gerard/reprint_mailer.pl?pref=53].

having said that, once you're faced with a near impossible molecular
replacement problem (and believe me, i've been there), you're probably going
to want to grab every straw, and that could well include homology models.
after all, you haven't got much to loose (apart from some time), and
everything to gain.

--dvd


> Following up on what Bart has said, I've been asked several times recently 
> whether or not one should use homology models for molecular replacement, in 
> preference to the original crystallographic model with the wrong sequence.  
> My (also biased?) impression is that homology modeling makes the models worse 
> for molecular replacement, and I have been suggesting that it's probably best 
> to stick to the original model, omitting only parts that are clearly very 
> different, and perhaps downweighting loops and side-chains that are likely to 
> fit poorly (as done in MolRep).
> 
> Of course, at some point the techniques of homology modeling will have 
> improved enough that the resulting models are actually better when the best 
> methods are applied carefully.  So the question is whether we're reaching, or 
> even nearing, that point yet.  It would be interesting if people could supply 
> clear-cut examples of where homology models were better for molecular 
> replacement than the original structures.  Does anybody out there have any 
> such examples?  Is my impression still correct, or is it finally out of date?

******************************************************************
                        Gerard J.  Kleywegt
    [Research Fellow of the Royal  Swedish Academy of Sciences]
Dept. of Cell & Molecular Biology  University of Uppsala
                Biomedical Centre  Box 596
                SE-751 24 Uppsala  SWEDEN

    http://xray.bmc.uu.se/gerard/  mailto:gerard@xray.bmc.uu.se
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