Re: [ccp4bb]: homology modelling?

[Bart Hazes <bhazes@ualberta.ca>]

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On Wed, 20 Nov 2002 gborgstahl@unmc.edu wrote:

> I was wondering what is the easiest way to apply a homologous sequence
> to a known crystal structure to create a homology model?

I just happened to come accross the following reference:

Increasing the precision of comparative models with YASARA NOVA--a
self-parameterizing force field.

Krieger E, Koraimann G, Vriend G. (Proteins 2002 May 15;47(3):393-402)

One of the conclusions drawn at the CASP4 meeting in Asilomar was that
applying various force fields during refinement of template-based models tends
to move predictions in the wrong direction, away from the experimentally
determined coordinates. etc...

In the paper they present a method that avoids/reduces this problem (I didn't
read the paper). Basically the question is whether current software will
create a model that is more similar to the real structure than the template
the model was based on. In the past my (biased?) impression was NO and the
paper above seems to confirm that. So unless the YASARA force field is an
acronym for "Your Atomic Structure Always Reliable & Accurate" I think
modeling should be approached with a properly sceptical attitude. The question
shouldn't be "what is the easiest way to apply a homologous sequence to a
known crystal structure" but what is the most accurate method and will it be
sufficient for the questions you have.

I have been recommending people not to make homology models at all. Just use
the template as is and your brain to extrapolate from the template. Of course
many of the more detailed questions cannot be answered this way but neither
can they by an inaccurate homology model and at least you won't get visually
fooled into believing things for which there really is no experimental
evidence. Just finding out where residues are relative to each other, buried
versus exposed, etc is very valuable and you don't need a homology model to
get that information.

Bart

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