summary for docking strategy

From: Dmitri V Mikhailov <mikha001;at;maroon.tc.umn.edu>
Subject: summary for docking strategy
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
 *****************************************************
 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: mikha001;at;maroon.tc.umn.edu
 *****************************************************
 >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
 **************************************************
 From p.grootenhuis;at;organon.akzonobel.nlMon Oct 14 09:46:59 1996
 Date: Fri, 4 Oct 1996 09:09:28 +0100 (WDT)
 From: Peter Grootenhuis <p.grootenhuis;at;organon.akzonobel.nl>
 To: Dmitri V Mikhailov <mikha001;at;maroon.tc.umn.edu>
 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 :
 p.grootenhuis;at;organon.akzonobel.nl
  _________________________________|____________________________________________
 **************************************************
 From maxwelds;at;carbon.dmpc.comMon Oct 14 09:47:17 1996
 Date: Fri, 4 Oct 1996 09:42:34 -0400
 From: David Maxwell <maxwelds;at;carbon.dmpc.com>
 To: Dmitri V Mikhailov <mikha001;at;maroon.tc.umn.edu>
 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,
 bill;at;adrik.chem.yale.edu.
 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:  maxwelds;at;carbon.dmpc.com
 ======================================================
 ************************************************
 From wasserzr;at;llaxp.dnet.dupont.comMon Oct 14 09:47:46 1996
 Date: Fri, 4 Oct 96 17:11:00 EDT
 From: wasserzr;at;llaxp.dnet.dupont.com
 To: Dmitri V Mikhailov <mikha001;at;maroon.tc.umn.edu>
 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