Subject: summary for docking strategy

From: Dmitri V Mikhailov <[email-masked]>
Date: Mon, 14 Oct 1996 10:06:14 -0500 (CDT)

Dear Netters,
About 10 days ago I posted question about docking strategy.
Thanks for everyone who replied. This information was really
helpful. My original question and answers are shown below.
Regards,
Dmitri Mikhailov
Ph.D. student
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Univ. of Minnesota Medical School
Department of Biochemistry
Box 609, 420 Delaware St. SE
Minneapolis MN 55455

tel. (612) 624-7107
fax. (612) 626-2325
e-mail: [email-masked]
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>Greetings everyone,
>We are trying to do docking analysis for a system composed of a
>negatively charged ligand and a basic protein. We are using the
>Affinity module from MSI which allows flexible docking.
>Could someone please point out reference(s) on general strategies
>how to incorporate explicit solvent molecules in such a system and
>analyze binding energies for different ligand conformations.
>Thank you.
>Regards,
>
>Dmitri Mikhailov
>Ph.D. student

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From [email-masked] Oct 14 09:46:59 1996
Date: Fri, 4 Oct 1996 09:09:28 +0100 (WDT)
From: Peter Grootenhuis <[email-masked]>
To: Dmitri V Mikhailov <[email-masked]>
Subject: docking

Dear Dmitri,
Check out our paper on docking negatively charged heparin derivatives on 
positively charged antithrombin III: JACS 1991, 113, 2743-2747. A better
job should be possible since computers are a lot fasternow. Please send me the
answers you get ...
Thanks,
Peter
 ______________________________________________________________________________
 Prof. Dr. Peter D.J. Grootenhuis |
 N.V. Organon / CMC Dept. RK2337  | Phone  : +31-412-661920
 P.O. Box 20 / 5340 BH Oss        | Fax    : +31-412-662539
 The Netherlands                  | E-mail : [email-masked]
 _________________________________|____________________________________________

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From [email-masked] Oct 14 09:47:17 1996
Date: Fri, 4 Oct 1996 09:42:34 -0400
From: David Maxwell <[email-masked]>
To: Dmitri V Mikhailov <[email-masked]>
Subject: Re: CCL:docking strategy

To be honest, I don't think that the version of Affinity that you have is
quite ready for prime time use.  I know this because I have been involved
in improving  the interface and working a little with the underlying code
We have been in contact with MSI about improvements and hope that future
versions will be better suited for docking.  "Affinity" is somewhat
misnamed as it is rather far from doing such calculations.

In terms of explicit solvent molecules are you interested in adding them in
the MSI calculations or are you looking for some other program which does
docking with explicit solvent?

If you are looking into calculating binding free energies (with explicit
solvent) I can suggest a program that I did some testing on back at Yale.
It is called MCPRO and is an extension of the BOSS program which handles
proteins.  I don't know what the current state is, but it has been used
successfully in a number of cases.  I did some testing on the sulfate
binding protein and learned quite a bit in the process.  If you want more
information please contact Prof. William Jorgensen via e-mail,
[email-masked].

Good luck!

-Dave

======================================================
Mail address:      Dr. David Maxwell
                   DuPont-Merck Pharmaceutical Company
                   Experimental Station E500-3206A
                   P.O. Box 80500
                   Wilmington, DE 19880-0500

Internet address:  [email-masked]
======================================================

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From [email-masked] Oct 14 09:47:46 1996
Date: Fri, 4 Oct 96 17:11:00 EDT
From: [email-masked]
To: Dmitri V Mikhailov <[email-masked]>
Subject: Docking Strategy question

This is in response to your question of analyzing binding energies 
for different ligand conformations.  I have been using a different 
implementation of the method of Affinity in studies of binding of 
negatively charged ligands to metalloproteases.

My initial endeavors are documented in "Fitting an Inhibitor Into the 
Active Site of Thermolysin: A Molecular Dynamics Case Study", Zelda R. 
Wasserman and C. Nicholas Hodge, PROTEINS: Structure, Function and 
Genetics, 24:227-237 (1996).  In short I find that the final total 
energy of the system, averaged over a short time span of a few picoseconds, 
correlates well with agreement with crystal structure conformation,
when such a conformation is known.

In addition, I find the "true" conformation is found in a small but
significant fraction of the simulations.  Cluster analysis of the
final conformations of a set of runs indicates this to be the major
cluster formed in just about every case I have looked at.  I have not
attempted to calculate or compare binding energies of different
ligands as I was dubious as to the validity of results.  Work done
here by my colleagues has shown those doubts to have been valid.

I have limited experience with explicit solvation and the Affinity
method.  The work of others indicates that addition of a few water 
molecules may or may not improve the calculation.  Full solvation
is possible but computationally demanding and we have no experience
in this area.

Zelda R. Wasserman
Principal Research Scientist
The Dupont Merck Pharmaceutical Company
Wilmington, DE 19880-0500