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Homology modelling

Robert W. Harrison harrison at calvin.jci.tju.edu
Wed Oct 19 14:18:08 EST 1994

In article <36nmhcINN2ng at bigbird.cc.williams.edu>, 95mhn at williams.edu (Kaspar Hauser MD) writes:
|> Hello,
|> 	Does anyone have any experience producing a very crude
|> structural hypothesis from sequence data?  We have Sybyl, but I've
|> been unable to get the Homology modeler to produce adequate results.
|> The situation is this:  I have a sequence-structure coordinate file of
|> a protein with > 85 % homology to the protein I want to make a
|> structure for, but Sybyl complains about not having enough short
|> regions of homology!  Are there any free programs that can do this?
|> I've tried Sybyls built in structure-seq database, and constructed my
|> own database with many similar proteins and just the resolved protein
|> with homology.  Any suggestions or references would be appreciated,
|> 				Max Nanao
|> 				95mhn at cc.williams.edu
|> 				nanao at ochre.mgh.harvard.edu

You should be able to do this in almost any molecular mechanics
program.  (The following is an advertisement - I can send you 
one that does not use cutoff radii and is as if not more
efficient that programs which use cutoffs, will run on anything, and
use almost any potential set  end of advertisement).  Basically
there are four tricks which help.

0) use an all-atom potential set.  IMHO you are wasting
your time with even the best united atom potential set.  We get
much more accurate results when using all-atom potentials when
we check structure and energies against experiment.

1) initially freeze (tether or restrain) the atoms from the
peptide backbone and identical side chain atoms to the
original positions.  Include crystallographically determined
water molecules.

2) build the missing side chains into the holes.  Sybil
should have a torsion search.  Distance geometric techniques
work as well.  Depending on the size of your protein, 
manual methods like FRODO or CHAIN are workable too. 
Minimize the energy of this (still frozen) structure.

3) let the whole thing relax.


					robert w. harrison
					harrison at asterix.jci.tju.edu

When in doubt, use brute force.
                -- Ken Thompson

For every complex problem, there is a solution that is simple, neat,
and wrong.
                -- H. L. Mencken


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