From chemistry-request@server.ccl.net Thu Jul 25 13:28:46 2002 Received: from mxout3.cac.washington.edu ([140.142.32.19]) by server.ccl.net (8.11.6/8.11.0) with ESMTP id g6PHSkr06606 for ; Thu, 25 Jul 2002 13:28:46 -0400 Received: from mailscan-out1.cac.washington.edu (mailscan-out1.cac.washington.edu [140.142.32.17]) by mxout3.cac.washington.edu (8.12.1+UW01.12/8.12.1+UW02.06) with SMTP id g6PHSfYu031275 for ; Thu, 25 Jul 2002 10:28:41 -0700 Received: FROM hymn07.u.washington.edu BY mailscan-out1.cac.washington.edu ; Thu Jul 25 10:28:40 2002 -0700 Received: from localhost (localhost [127.0.0.1]) by hymn07.u.washington.edu (8.12.1+UW01.12/8.12.1+UW02.01) with ESMTP id g6PHSejn029573 for ; Thu, 25 Jul 2002 10:28:40 -0700 Date: Thu, 25 Jul 2002 10:28:40 -0700 (PDT) From: Christophe L M J Verlinde To: chemistry@ccl.net Subject: free energy calc In-Reply-To: Message-ID: MIME-Version: 1.0 Content-Type: TEXT/PLAIN; CHARSET=US-ASCII Dear CCLers, We have been trying to "predict" the free energy change for replacing a neutral inhibitor bound to a protein into an isosteric one with a -1 charge via a thermodynamic cycle. Our approach consists of MD simulations with and explicit waters (TIP3P). We have tried both FEP and TI. We also experimented with particle mesh Ewald techniques. The bottom line is that the calculations are off by 2.5 to 5 kcal/mol > from reality depending on the protocol (we used the AMBER6 package). The problem probably does not reside in proper sampling as the simulations reproduce the conformational change seen between the 2 complexes (we have high resolution X-ray structures). Has anyone had any success with such type of simulations, i.e. cases involving a net change in charge? If so, could you provide us with recommended protocols. Thanks Christophe L.M.J. Verlinde Biomolecular Structure Center University of Washington - Box 357742 Seattle, WA 98195 T:(206)543-8865 F:(206)685-7002 URL: www.bmsc.washington.edu/people/verlinde