From chemistry-request@ccl.net Mon Sep 8 09:04:22 2003 Received: from web13504.mail.yahoo.com (web13504.mail.yahoo.com [216.136.175.83]) by server.ccl.net (8.12.8/8.12.8) with SMTP id h88D3pB8015653 for ; Mon, 8 Sep 2003 09:03:51 -0400 Message-ID: <20030908130350.15007.qmail(at)web13504.mail.yahoo.com> Received: from [130.238.38.182] by web13504.mail.yahoo.com via HTTP; Mon, 08 Sep 2003 06:03:50 PDT Date: Mon, 8 Sep 2003 06:03:50 -0700 (PDT) From: Subject: Docking of large molecules ~ 16-20 rotatable bonds To: chemistry(at)ccl.net MIME-Version: 1.0 Content-Type: text/plain; charset=us-ascii X-Spam-Status: No, hits=0.8 required=7.0 tests=NO_REAL_NAME version=2.55 X-Spam-Checker-Version: SpamAssassin 2.55 (1.174.2.19-2003-05-19-exp) Dear all, Does anyone know a good way to dock molecules with 20 rotatable bonds ? Any kind of information is appreciated. Thank you. ===== Yogesh Sabnis, PhD BMC, Box 574, Avd Org. Farm. Kemi, Husargatan 3, Uppsala - 75123 Sweden __________________________________ Do you Yahoo!? Yahoo! SiteBuilder - Free, easy-to-use web site design software http://sitebuilder.yahoo.com From chemistry-request@ccl.net Mon Sep 8 15:07:31 2003 Received: from ccl.net (email.ccl.net [192.148.249.4]) by server.ccl.net (8.12.8/8.12.8) with ESMTP id h88J70B8006995 for ; Mon, 8 Sep 2003 15:07:00 -0400 Received: from krakow.ccl.net (krakow.ccl.net [192.148.249.195]) by ccl.net (8.11.6+Sun/8.11.6/OSC 2.1) with ESMTP id h88J6xm09418; Mon, 8 Sep 2003 15:06:59 -0400 (EDT) Date: Mon, 8 Sep 2003 15:06:59 -0400 (EDT) From: "Dr. Jan K Labanowski" To: chemistry.-at-.ccl.net cc: sue.-at-.sura.org Subject: 03.10.20 3rd Annual Computational Chemistry Conference Message-ID: MIME-Version: 1.0 Content-Type: TEXT/PLAIN; charset=US-ASCII X-Spam-Status: No, hits=0.0 required=7.0 tests=USER_AGENT_PINE version=2.55 X-Spam-Checker-Version: SpamAssassin 2.55 (1.174.2.19-2003-05-19-exp) The 3rd Annual Computational Chemistry conference will be held at the University of Kentucky, Lexington, October 20 & 21, 2003. Information about the program, housing and registration may be found at http://www.sura.org . Please note that there is NO registration fee for this conference. Sue Fratkin IT Consultant SURA From chemistry-request@ccl.net Mon Sep 8 16:40:49 2003 Received: from mercure.neokimia.com (mercure.med.usherbrooke.ca [132.210.158.207]) by server.ccl.net (8.12.8/8.12.8) with ESMTP id h88KeEB8013847 for ; Mon, 8 Sep 2003 16:40:17 -0400 Subject: CCL: RE: Docking of large molecules ~ 16-20 rotatable bonds Date: Mon, 8 Sep 2003 16:38:28 -0400 MIME-Version: 1.0 Content-Type: text/plain; charset="iso-8859-1" Message-ID: X-MS-Has-Attach: X-MIMEOLE: Produced By Microsoft Exchange V6.0.6249.0 X-MS-TNEF-Correlator: content-class: urn:content-classes:message Thread-Topic: CCL: RE: Docking of large molecules ~ 16-20 rotatable bonds Thread-Index: AcN2Ek+1IIwSBDpgT6CyE7Gnvu/caAAL9ITw From: "Axel Mathieu" To: , X-Spam-Status: No, hits=0.0 required=7.0 tests=none version=2.55 X-Spam-Checker-Version: SpamAssassin 2.55 (1.174.2.19-2003-05-19-exp) Content-Transfer-Encoding: 8bit X-MIME-Autoconverted: from quoted-printable to 8bit by server.ccl.net id h88KenB8013870 I've been docking 15-20 membered macrocycles with side-chains (20-30 rotatable bonds including the macrocyclic backbone). Unfortunately, not too many programs can handle these molecules appropriately so I've had to try several methods before coming up with a method that I'm comfortable using on a large scale basis. First of all, expect this project to take up large amounts of time to get an answer that actually means something (at least more time than what most people publish). Due to the macrocyclic nature of the molecules I dock, the solution was as follows: 1) Perform a complete conformational search of the molecules of interest. This is by far the longest step but the most important and its quality will depend on the algorithm you use and the limits you set (since we're looking for molecules that bind, and that the macrocycles are used to conformationally constrain the molecules, I've limited the search within 3 kcal, even less on particular cases). 2) Use a good docking algorithm and rigidly dock each conformer. I know this sounds like ancient technology since everybody is looking at solving flexible ligands and receptors. The fact is that if you were to perform flexible docking of large molecules like these on flexible receptors, you better have access to a cluster. Moreover, the conformational search is "portable" and can then be used on different targets or different rigid conformers of the original target - rigid docking is extremely fast!!! You're also certain that you're testing the most feasible preoganized structures that should fit in the receptor (which should start becoming a factor at this molecular size, depending on you're the functional groups present). One of the most interesting points to this is that you can also use these conformational searches for pharmacophore queries ... take a look at John H. van Drie. Pharmacophore Discovery - Lessons Learned. (2003) Current Pharmaceutical Design, 9, 1649-1664. 3) In some cases (depending on your docking algorithm), you may even have to add an additional optimization step to the docked solutions. This solution was by far my best option with the software I had for several reasons: 1) To start, the docking algorithm had difficulty dealing with a flexible macrocycle (the macrocycle is my biggest challenge - no software that I know of is actually designed for this. I even have problems with the forcefields)! 2) We believe that the lowest energy conformers are the binding conformers (this is the whole point to using macrocycles isn't it?!) and if a different shape is need, a different macrocycle should be used! And 3) I did not have access to a cluster. If you get more answers, could you please forward them to me, I'm interested in what others have experienced also. If your problem is "linear", you may find good and fast docking algorithms that build you molecules as they are docked. The problem that I have with these is, as I mentioned before, preorganization. Large molecules, although packed with random domains, should retain some core structure(s) maintained by intramolecular interactions. I have a difficult time believing that the build-up docking algorithms will take this into consideration. Unfortunately, large linear molecules will produce large amounts of conformers so choose your algorithm, simulation system, and cut-offs carefully. Oh by the way, I had to come up with my own scoring method for molecules of this size since the ones available in my software were very pool at identifying the known pose for a crystallized pentapeptide ligand binding to a solvent accessible binding site ... have fun and be patient, you'll probably need it!! ;o) APM -----Original Message----- From: ysabnis^at^yahoo.com [mailto:ysabnis^at^yahoo.com] Sent: 8 septembre, 2003 09:04 To: chemistry^at^ccl.net Subject: CCL:Docking of large molecules ~ 16-20 rotatable bonds Dear all, Does anyone know a good way to dock molecules with 20 rotatable bonds ? Any kind of information is appreciated. Thank you. ===== Yogesh Sabnis, PhD BMC, Box 574, Avd Org. Farm. Kemi, Husargatan 3, Uppsala - 75123 Sweden __________________________________ Do you Yahoo!? Yahoo! SiteBuilder - Free, easy-to-use web site design software http://sitebuilder.yahoo.com -= This is automatically added to each message by the mailing script =- To send e-mail to subscribers of CCL put the string CCL: on your Subject: line and send your message to: CHEMISTRY^at^ccl.net Send your subscription/unsubscription requests to: CHEMISTRY-REQUEST^at^ccl.net HOME Page: http://www.ccl.net | Jobs Page: http://www.ccl.net/jobs If your mail is bouncing from CCL.NET domain send it to the maintainer: Jan Labanowski, jkl^at^ccl.net (read about it on CCL Home Page) -+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+ From chemistry-request@ccl.net Mon Sep 8 16:09:51 2003 Received: from sgofims02.ccs.ppg.com (smtpout.ppg.com [141.189.251.4]) by server.ccl.net (8.12.8/8.12.8) with ESMTP id h88K9IB8011399 for ; Mon, 8 Sep 2003 16:09:19 -0400 Received: by sgofims02.ccs.ppg.com with Internet Mail Service (5.5.2653.19) id ; Mon, 8 Sep 2003 16:09:09 -0400 Message-ID: <3251EC702A37B9458A01D917C3D3B389034FEF$at$sgofusr20.nac.ppg.com> From: "Deng, Jun" To: chemistry$at$ccl.net Subject: solvent effect Date: Mon, 8 Sep 2003 16:09:11 -0400 MIME-Version: 1.0 X-Mailer: Internet Mail Service (5.5.2653.19) Content-Type: text/plain; charset="iso-8859-1" X-Spam-Status: No, hits=0.0 required=7.0 tests=none version=2.55 X-Spam-Checker-Version: SpamAssassin 2.55 (1.174.2.19-2003-05-19-exp) Dear Colleagues: I am using G98 to calculate the Gibbs free energy of the reaction in the solvent. The reaction involve ionic species, so the solvent effect is important. Here is what I did: 1. Gas phase geometry optimization and freq calculation 2. Using PCM to calculate single point energy 3. Add thermal correction energy from gas phase to single point energy calculated in solvent. Strictly, I think it is better to do geom. optimization and freq. calc. in solvent. However, I couldn't do this in G98 with PCM. Do you have any experience in how important it is to calculate reaction energy with optimized geometry and freq in solvent? Thanks in advance, Jun Deng From chemistry-request@ccl.net Mon Sep 8 21:02:13 2003 Received: from dasher.wustl.edu (dasher.wustl.edu [128.252.208.48]) by server.ccl.net (8.12.8/8.12.8) with ESMTP id h8911gB8007017 for ; Mon, 8 Sep 2003 21:01:42 -0400 Received: from dasher.wustl.edu (adsl-64-218-90-170.dsl.stlsmo.swbell.net [64.218.90.170]) by dasher.wustl.edu (8.11.0/8.11.0) with ESMTP id h890wWr263574; Mon, 8 Sep 2003 19:58:32 -0500 (CDT) Message-ID: <3F5D288F.2000900[at]dasher.wustl.edu> Date: Mon, 08 Sep 2003 20:10:39 -0500 From: Jay Ponder Reply-To: ponder[at]dasher.wustl.edu Organization: Washington University, Biochemistry User-Agent: Mozilla/5.0 (X11; U; Linux i686; en-US; rv:1.4) Gecko/20030624 Netscape/7.1 X-Accept-Language: en-us, en MIME-Version: 1.0 To: chemistry[at]ccl.net Subject: TINKER 4.1 and Force Field Explorer 1.1 are Available Content-Type: text/plain; charset=us-ascii; format=flowed Content-Transfer-Encoding: 7bit X-Spam-Status: No, hits=-0.1 required=7.0 tests=USER_AGENT_MOZILLA_UA,X_ACCEPT_LANG version=2.55 X-Spam-Checker-Version: SpamAssassin 2.55 (1.174.2.19-2003-05-19-exp) Dear Computational Chemistry List, A new release of the TINKER Molecular Modeling Package, version 4.1, is available from the Ponder Lab web site at http://dasher.wustl.edu/ or via anonymous ftp from dasher.wustl.edu in the /pub/tinker area. TINKER 4.1 is a modular, general package for molecular mechanics and dynamics with some special features, facilities and parameter sets for biopolymers. It currently supports several force fields, including Amber (ff94, ff96, ff98 and ff99), CHARMM (19 and 27), Allinger MM (MM2-1991 and MM3-2000), OPLS (OPLS-UA, OPLS-AA and OPLS-AA/L) and our own AMOEBA polarizable atomic multipole force field. The software contains many advanced algorithms for energy minimization, molecular dynamics, distance geometry and global search, including some methods that are not readily available elsewhere. Changes from TINKER 4.0 include some new force field parameter sets, improvements to rigid body dynamics, a Nose-Hoover thermostat, and numerous minor additions and bug fixes. In addition, release of TINKER version 4.1 coincides with a new version 1.1 of the Force Field Explorer visualization program and GUI for the TINKER package. This new version of FFE contains major improvements over the initial 1.0 release: (1) the communication between TINKER and FFE is now via Java sockets, leading to much greater stability, (2) tighter integration with the TINKER programs, (3) improved video performance and speed, (4) many added features and improvements to the easy-of-use of the interface. TINKER and Force Field Explorer are distributed with full source code, a User's Guide, and several examples and test molecule files. Directions are supplied for building the package on most commonly used CPU/OS combinations. Prebuilt executables limited to a maximum of 10000 atoms are also provided for Linux, Windows and Mac OS X. The Linux and Windows executables are fully GUI-capable. Please see the web site above for further information. We ask those who make significant use of TINKER to complete, sign, and return by regular mail the license form available on our web site. We keep all the returned forms and use them to help justify further development of the package. Comments, questions and suggestions for improvements should be sent to ponder[at]dasher.wustl.edu. We are particularly eager to get feedback > from people who are considering using TINKER and Force Field Explorer in an instructional setting. Best wishes, Jay Ponder -- Jay W. Ponder Phone: (314) 362-4195 Biochemistry, Box 8231 Fax: (314) 362-7183 Washington University Medical School 660 South Euclid Avenue Email: ponder[at]dasher.wustl.edu St. Louis, Missouri 63110 USA WWW: http://dasher.wustl.edu/