From mikha001*- at -*maroon.tc.umn.edu Mon Oct 14 11:14:51 1996 Received: from mhub2.tc.umn.edu for mikha001 #at# maroon.tc.umn.edu by www.ccl.net (8.8.0/950822.1) id LAA23572; Mon, 14 Oct 1996 11:06:15 -0400 (EDT) Received: from maroon.tc.umn.edu by mhub2.tc.umn.edu; Mon, 14 Oct 96 10:06:15 -0500 Received: by maroon.tc.umn.edu; Mon, 14 Oct 96 10:06:15 -0500 Date: Mon, 14 Oct 1996 10:06:14 -0500 (CDT) From: Dmitri V Mikhailov To: chemistry*- at -*www.ccl.net Subject: summary for docking strategy Message-ID: MIME-Version: 1.0 Content-Type: TEXT/PLAIN; charset=US-ASCII 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 To: Dmitri V Mikhailov 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 -8 at 8- organon.akzonobel.nl _________________________________|____________________________________________ ************************************************** From maxwelds -A_T- carbon.dmpc.comMon Oct 14 09:47:17 1996 Date: Fri, 4 Oct 1996 09:42:34 -0400 From: David Maxwell To: Dmitri V Mikhailov 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 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