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

From: "Dr. Csaba Hetenyi" <csaba..at..ovrisc.mdche.u-szeged.hu>
Date: Mon, 6 Sep 2004 15:14:38 +0200 (CEST)

> Does this mean that computational docking is not 
> useful in a practical sense?

No, docking can be validated for a target and it is reliable if validated.
I prefer using X-ray structures as targets during docking. If no
measured structure is available, HM may be the way to get something
like the real target could be. Of course, quality of the model depends
on information used for building it. In some cases, e.g. in case of
smaller, peptide-like targets spectroscopic methods (IR, NMR, CD) could
provide some info on secondary structure or constraints, which could be
used for HM or de novo model building. Similarity between biological 
activities of a known and HMed protein could also help.

> And what do you think about high-throughput 
> homology modeling set-ups (ModBase,...)?

However, there is no appropriate scheme for HM
which could be used for any proteins and automated HM seems a dream for
me. Validation is my central problem with HM. Proteins can be so different
even within a family, that there is no surety of the precison of the model
of an unknown protein.
It would be interesting to collect more opinions on this topic to make a
clear picture of HM.
Best wishes,
Csaba

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From: "Dr. Csaba Hetenyi" <csaba_at_ovrisc.mdche.u-szeged.hu>
Date: Mon, 6 Sep 2004 17:38:12 +0200 (CEST)

> > 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.
> 
> 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:

This example was used for demonstrating uncontrolled and failed HM. The
authors refer to different homology models resulting structures far from
their measured structure. The referred HMs were used for docking
extensively, as i could follow from the literature. These HM->docking
works caused pain for me...:)
In my view, further clarification of general rules of HM and careful work 
would be necessary to avoid such mistakes...
Best,
Csaba