Subject: RE: RE:Protein force fields

From: <[email-masked]>
Date: Fri, 03 Dec 1993 12:43:46 +0000

Dear Chuck,

As it happens I have just reviewed the Rao and Teeter paper for our journal
club.  I chose the paper for 3 reasons: a) It was being presented to 
biochemists, b) I am a computational chemist, c) I liked the practicality
of the approach.

Martha Teeter is a crystalographer who has a long standing interest in proteins
related to a-purothionin (eg crambin which she also solved), but has limited
access to computing facilities (Microvax II).  She clearly wants to find a
method that gives a good guess for solving protein structures by x-ray
methods.  The paper presents a VERY rudimentary MD simulation using the
AMBER UA force field, in vacuo, with much of the structure constrained.  This
is a very simple and unsophysticated approach, and in some ways it is perhaps
pleasantly surprising that it worked.  However, there are a few notable
points:

1) This is a purely anecdotal report.
2) Alpha-PT is highly homologous to Crambin and so a very good guess for the
   MM/MD calculations was already available.
3) The MD was performed on a very small subset of the atoms (6 out of 46 
   residues only).
4) Because of the particular nature of this protein (and its homologs) the
   ends of the critical loop-region could be assumed to be in the correct
   conformation, therefore extensive conformational restraints could be
   invoked.
5) The authors report that an unconstrained MD simulation (epsilon=1,in vacuo)
   resulted in [hydrogen] bond breaking, but apparently did not test the
   stability with (epsilon=4) which they went on to use for the partial
   MD.
6) Although the authors refer to a 2ps equilibration period, there PE
   data clearly shows equilibration was not reached until about 30 ps. This
   is unimportant in context of their analysis, but without continuing the
   trajectory for a longer period it is not possible to say how stable their
   loop conformation really is.

The results are however interesting, particularly the sequential nature of
the changes in the backbone conformation.  I think that if the system can be
modelled based on similar high homology the UA approach looks very interesting,
but it is very system dependant.  It worked in this case but I think solvation
would have to be considered for more general studies.

Hope this sparks other comments and answers some of your questions,

Best wishes,

Rob Woods

Robert J. Woods, Ph.D.
Glycobiology Institute
Department of Biochemistry
University of Oxford
South Parks Road
Oxford, OX1 3QU
England