Subject: SUMMARY: secondary struct. to protein models

From: "Jerome Baudry" <jerome|at|scs.uiuc.edu>
Date: Tue, 27 Apr 2004 09:41:07 -0500

Dear list

A couple of weeks ago I asked about ides and references on how to assemble
NMR-obtained secondary structure assignments of protein domains into a
possible ensemble of protein structure(s). Apparently, there is no clear
roadmap to do such a think. Several solutions exist to evaluate the quality
of a protein structure, e.g. Sippl's approaches or Profile3D-like
approaches, but assembling several protein domains into one protein
structure seems to be a field in progress. Work in this direction is based
on protein-protein interaction approaches e.g. FTDOCK and others, and on
threading approaches. I received several good ideas and references. Thanks
to all. I include here a summary of the emails I get.

----------------------------------------------------------
Jerome Baudry, Ph.D.       Senior Research Scientist, VizLab Manager.
School of Chemical Sciences    University of Illinois at Urbana-Champaign
505 S. Mathews Ave.; Box 2.1; Urbana, IL, 61801
 Phone: (1) (217) 244 3210; Fax: (1) (217) 333 3120;    e-mail:
jerome|at|scs.uiuc.edu

==== SUMMARY ===

You may want to have a look a Dobrodumov and Gronenborn (2003) Proteins:
Structure, Function, and Genetics 52, 18-32. In order to apply their
approach, you
will need to measure RDC data for the intact protein.
Keith Constantine, BMS
====

Have a look at "Multiscale Modeling Tools in Structural Biology" tool set:
http://mmtsb.scripps.edu/. It allows you to pass to lattice description of
the protein, fix the secondary structure elements and run minimization by
replica exchange algorithm. The final low-energy conformations can be
converted back to atomistic models and, possibly, refined by using more
realistic force field/solvation schemes (say CHARMM22 + GBSA).
Andriy Baumketner, UCSB
====

I do not know of a program that could do what you are proposing,
although we have been thinking of automating such a process
with our combinatorial stochastic elimination algorithm (PNAS 99, 703
(2002)).
In the meantime, it seems to me that you could possibly get a few
alternatives by running MD with constraints on your secondary structure
elements, in various temperatures, and "cool down" by simulated annealing
or by regular minimization, at many different points along the MD.
Amiram Goldblum, Hebrew University

====
Looking at this problem from another perspective, maybe you don't need to
generate models and evaluate them. Have you thought about doing some sort of
'threading' with your sequence of secondary structure elements? Find the
known structures could be compatible with what you know about the sequence
of secondary structure elements? Such threading should recognize structural
homology where sequence homology was not high enough to detect.
You might be able to use existing sequence alignment tools, but use a
sequence that says, HHHHTTTTSSSSSSSSSSSRRRHHHHHHHHH, etc. Generate a
template from your information and a library from the pdb. The advantage of
using sequence alignment software is that it will already know about gaps,
insertions and deletions in generating a score.
Jeff Bell, Accelrys

====
How about a PMF derived from a statistical analysis of the information? This
could be easily represented as a scoring function. I think a full potential
energy function is overkill for this. A good source of information would be
papers on PMF's for threading my people like Manfred Sippl, Jeff Skolnick,
Adam Godzik, etc. In its essence, this is very much the kind of information
fold recognition programs use, except that they analyse pdb structures.
Programs like David Eisenberg's SeqFold, essentially do fold recognition
using secondary structure.
Deepak Singh (Accelrys)

+ thanks to UCSD's Stewart Adcok for information about his lab's current
work in this field.