Subject: Re: CCL:predict 3D structure from sequence (fwd)

From: Dominique Vlieghe <dominique.vlieghe)at(dmbr.ugent.be>
Date: Mon, 06 Sep 2004 14:22:10 +0200

Dr. Csaba Hetenyi wrote:

>>The first one called Camparative Protein Modeling, which requires a 3d
>>structure of a protein, which has >30% sequence Similarity comparing to
>>target. It's pretty reliable.  The second approach has lower success
>>rate..
>>    
>>
>
>I'd rather not say "it is pretty reliable". In my view, sequence
>similarity (30 % or above) is not a sufficient only a necessary
>requirement of possible homology modeling (HM).
>A "nice" example of failure of HM was recently mentioned in Williams et
>al. Science 305 (2004) 683-686. E.g. CYPs are "excellent" examples of
>proteins not appropriate for HM. 
>Extensive, uncontrolled use of HM (or - horribile dictu - HM and
>consecutive docking on a HMed target contributes to rising (and - in this
>case - right) scepticism of experimental guys against modeling (against
>us).
>  
>
Sadly, I must say from personal experience I agree with you, but the 
problem remains that one often has to homology model a given receptor, 
because a xray/nmr structure is lacking.  We as end-users of docking 
algorithms cannot wait for the experimental structures, because it is 
almost always the case that the crystal structure is one of the last 
pieces of information that is available (i.e. an experimental validation 
of a certain protein-ligand interaction has been published before the 
structures are known). Does this mean that computational docking is not 
useful in a practical sense? And what do you think about high-throughput 
homology modeling set-ups (ModBase,...)?

Regards

Dominique

>Sorry, if i was too negative concerning HM.
>Best wishes,
>Csaba
>
>
>
>
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-- 
------------------------------------------------------------------------
Save the Hubble petition: http://www.savethehubble.org
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Dominique Vlieghe, Ph.D.,
Bioinformatics Core, Department for Molecular Biomedical Research (DMBR)
VIB - Ghent University
Technologiepark 927, B-9052 Ghent (Zwijnaarde), Belgium
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email: dominique.vlieghe)at(dmbr.ugent.be           tel: +32-(0)9-33-13.693
www: http://www.dmbr.ugent.be/                   fax: +32-(0)9-33-13.609
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From: "Felipe Pineda, PhD" <pineda)at(imb-jena.de>
Date: Mon, 06 Sep 2004 12:35:58 +0200

Dear Csaba and all,

> proteins not appropriate for HM.

According to your own necessary/sufficient conditions this wouldn't be a
good
example, since the authors state that templates available for
comparative modeling
of CYP3A4 display just sequence identities < 30% with the target. On p.
684 you
can read:

"The most widely used templates for modeling CYP3A4 are the P450
structures from
Bacillus megaterium (P450 BM3) and Saccharopolyspora erythraea (P450
EryF), both
of which share less than 25% sequence identity with CYP3A4."

Without the intension of self-advertising, I can refer you to our
(Hillisch, A.,
Pineda, L.F. and Hilgenfeld, R.) recent paper published on DDT
9(2004)659-669 on
the utility of homology models in the drug discovery process, wich
contains a, in
our opinion, balanced discussion on the performance of the comparative
modeling
method in different applications.

Best regards

Felipe