From CTARG@Levels.UniSA.Edu.Au Wed Jul 6 06:52:56 1994 Received: from Levels.UniSA.Edu.Au for CTARG@Levels.UniSA.Edu.Au by www.ccl.net (8.6.9/930601.1506) id WAA21699; Tue, 5 Jul 1994 22:48:43 -0400 From: Received: from Levels.UniSA.Edu.Au by Levels.UniSA.Edu.Au (PMDF V4.3-8 #6043) id <01HEDWE4RIE8A9LFUY@Levels.UniSA.Edu.Au>; Wed, 06 Jul 1994 12:18:38 +0930 Date: Wed, 06 Jul 1994 12:18:38 +0930 Subject: specifying atomic charges in MOPAC To: chemistry@ccl.net Message-id: <01HEDWE4TX7MA9LFUY@Levels.UniSA.Edu.Au> X-Envelope-to: chemistry@ccl.net X-VMS-To: IN%"chemistry@ccl.net" MIME-version: 1.0 Content-type: TEXT/PLAIN; CHARSET=US-ASCII Content-transfer-encoding: 7BIT Hi Netters, Is it possible to specify charges for given atoms using MOPAC93? The charge of the entire system can be specified using CHARGE=. Or alternatively is there a way of telling the calculation that the system you want to look at is entirely ionic? Thanks Andy. From D.Winkler@chem.csiro.au Wed Jul 6 07:37:07 1994 Received: from auric.chem.csiro.au for D.Winkler@chem.csiro.au by www.ccl.net (8.6.9/930601.1506) id BAA22043; Wed, 6 Jul 1994 01:33:00 -0400 Received: from chem.csiro.au ([138.194.40.143]) by auric.chem.csiro.au with SMTP id AA06313 (5.67b/IDA-1.5 for chemistry@ccl.net); Wed, 6 Jul 1994 15:30:38 +1000 Date: Wed, 6 Jul 94 15:32:50 EST From: "Dr. Dave Winkler" Subject: Summary: success stories in molecular design (long) To: chminf-l@iubvm.ucs.indiana.edu, chemistry@ccl.net X-Mailer: LeeMail 2.0.4 Message-Id: Here is a summary of the responses. Thank you very much to all who replied. By the way, the first success in comp.-aided molecular modeling in Japan might be ACE inhibitor from Takeda. They developed CV-3317(?), that is in market now, and they analized usign extended huckle. And they found 7-membered ring is very much stable and suitable conformer. Then they developed 7-membered ring derivatives. Among them, CV-597X(?) was chosen. After that I do not know. Please ask Dr.Kamiya(Takeda). And Sankyo researchers developed gastrin antagonist using gastrin as a template about 10 years ago. I do not well about this. I am sorry. I searched and found the literatures. They only reported the compounds. K.Itoh et al., Chem.Pharm.Bull.,34,1128,2078,3747(1986). He presented only at the symposium about calculations. He used MM2 and extended Huckel to calculate CV3317 and cyclic compounds. They took X-ray structure of CV-3317, and found that the methyl group and indane ring is very near. Thus, he calculated 6-membered ring as 54kcal/mol, 7-membered ring as 0.8kcal/mol, 8- as 0.7, and 9- as -0.4. And at last they found CV-5975. ____/ ___/ ___/ Yoshihisa INOUE (^_^) the Green Cross Corp. / / / 2-25-1 Shodai-Ohtani,Hirakata,Osaka 573 JAPAN / _ / / / tel: +81-720-56-9328 / / / / fax: +81-720-68-9597 _____/ ____/ ____/ E-mail: inoue@greencross.co.jp ======================================================== Gange, D. M., S. Donovan, and K. Henegar "The Design of Insecticidal Uncouplers." 207th American Chemical Society National Meeting, San Diego, Calif., March 13-17, 1994 COMP 171 The discovery of the potent insecticide pyrrolomycin in 1985 led to an intensive study of the properties pf pyrrolomycin and related pyrrole insecticides. Mitochondrial assays indicated that the mode of action of the pyrroles was uncoupling. The compounds uncouple respiration from phosphorylation, preventing the synthesis of ATP. A QSAR model describing the activity of the pyrroles has been developed. The development of the model and the use of the model to predict the activity of a new class of uncouplers will be discussed. To contact the lead author, please send email to ganged@pt.Cyanamid.com --David Saari saarid@pt.Cyanamid.com ========================================================= One of the research scientists here at the American Cyanamid Company Agricultural Research Division successfully predicted the biological activity of a series of potentially commercial agrochemical compounds. I don't know how much of this research has been cleared for release to the public so I can't give details without checking to see if the research has been published or disclosed at a scientific meeting, etc., (patentability considerations, you know). In this case, I can say that the research was not a "black box" situation. The computational chemistry was a tool for predicting possible activity. Nevertheless, chemists did have to make the compounds, and our screening people had to run the tests to confirm biological activity. --David Saari saarid@pt.Cyanamid.COM =========================================================== Hi Dave-- Glad to have a chance to make your aquaintance! This is sitting on my hard drive, so I don't even have to try myself, or suggest you try Jan's "search" thing... John reissner@argon.chem.ucla.edu Ph: (310)825-5151; Fax: (310)206-3566 Dep't Chem and Biochem, MC 156905, UCLA, 405 Hilgard Ave., LA 90024- 1569 Home: 972 Hilgard Ave., Apt. 302, Los Angeles, CA 90024 Ph: (310)824-1732 ****************************************************************************** The 'classic' example you seek is Mark von Itzstein and Peter Colman's work on neurimidase inhibitors as anti-flu drugs. Their very first do novo inhibitor is in second stage trials and there are much better ones coming along behind. See the recent cover story in Nature. Dr. David A. Winkler D.Winkler@chem.csiro.au ******************************************************************************* About two or three years ago, Hoffmann-La Roche of Switzerland brought the first "designed" drug to the market. It is a drug that passes the blood/brain barrier, and is converted by an ezymatic reaction in the brain to the active compound. The pre- drug was modelled for that enzyme. As far as I know, the German chemical and pharmaceutical industries use Molecular Modelling extensively. following their demand, there have been several new position for computational chemistry professors founded during the past five years to teach students the basics of modelling. Dr. Rainer Stumpe INTERNET:STUMPE@SPINT.COMPUSERVE.COM ******************************************************************************* ........ Drug companies and other chemical manufacturers are not going to tell you about this even if they have an example. This type of stuff is usually proprietary. .......... How then should CC be viewed? I think an excellent analogy is the way we think about the analytical chemistry (AC) division of any large res- earch operation. AC supports efforts in all phases of the research process. However, the mass spec guy is never asked "What specific drug product is that there $500,000 GC/MS dohicky responsible for?" Everyone recognizes that the mass spec is part of the effort, and things would be crippled without it. This is how CC should be integrated into the research/discovery process. There are several models on how to include CC in a company's effort. In one, the CC guys are a consulting group that works with people that bring them specific problems. In another, each effort has one or more CC guys IN the group. Both are valid and both seem to be producing results. CC is good are predicting trends and in focusing experimental investigations, which are fairly expensive these days. CC should be part of every research problem in a modern setting. PART, I said, not WHOLE. Alot of the recent "backlash" against CC is due to overselling. If we CC folk expect to survive, we don't need to oversell the results that we can provide, but honestly point out what CC should be doing. To finish, I'll tell a little story. When I was interviewing for a job on leaving the Dewar group about 6 years ago, I visited the research labs of a large midwestern polymer manufacturer. I was shown a lab with 4 PhD polymer chemists in it. Each was required to make 1 new polymer blend per week. These blends then went to physical testing for evaluation as new products. The company expected to get one new CANDIDATE for a new product each year out of that lab. Seems a bit cost prohibitive doesn't it? They asked me how CC could help them. Back then, the answer was much less positive than it is now, but even then, CC could have helped them focus their efforts more directly and greatly enhanced the "hit rate." IMHO, that's what we do best. ........... Andy Holder University of Missouri - Kansas City || Internet Addr: aholder@vax1.umkc.edu ******************************************************************************** Hello, There are numerous examples of "designed" compounds that have biological activity. Unfortunately, many companies do not reveal this information. You should consult the December 1993 issue of Scientific American for a well written article by Charlie Bugg et al. Phil Bowen Computational Center for Molecular Structure and Design Department of Chemistry University of Georgia ******************************************************************************* Agouron Pharmaceuticals has published work on de novo design of inhibitors to thymidylate synthase; some of these inhibitors are in clinical trials. Ciba-Geigy and BioCryst have published work on de novo design of inhibitors of purine nucleoside phosphorylase; I think one of these may also be in trials. DuPont-Merck has a paper in press in Science describing their de novo design and crystallographic verification of a potent, nonpeptide HIV protease inhibitor. This compound is also in clinical trials. Jeff Blaney Chiron ******************************************************************************* Certainly all of the HIV-protease inhibitors fit into your category. Abbott has at least one in clinical trial. The big splash was the DuPont-Merck cyclic urea , but SmithKline also designed a similar compound. The former is in the clinic I think; I don't know about the latter. Additionally, the renin inhibitors were designed, usually from modeled structures. Alex Vlodower and John Erickson have a recent review on the HIV protease inhibitors. Yvonne Martin Abbott Laboratories There was also a recent ACS Satellite Symposium on the topic. >From MARTIN@CMDA ******************************************************************************* I'm not aware of those that have reached market or clinical trails but, there was a article about the process this year: J.Montgomery, S.Niwas, Structure Based Drug Design, CHEMTECH 23(11) November 1993, 30 Charles G James Chemistry Department University of North Carolina at Asheville. One University Heights Asheville, NC 28804-3299 Phone: 704-251-6443 james@unca.edu ******************************************************************************** There are a few examples which come close to being De novo designed, but I've olny heard these discussed at conferences (even these used a large amount of physical data in the models). A recent scientific american article should leed you in the right direction. Scientific American December 1993 Drugs by Design 92-98 C.E.Bugg W.M.Carson J.A.Montgomery Regards, Mike Miller ******************************************************************************* In the December 1993 issue of Scientific American, p.92 there is a good article "Drugs by Design." At the end of the article, p. 98, there are listed some drugs that were designed. I know that Agrouon's molecules are in Phase I trials, one in England and one in the States. They were developed from the tertiary structure of the enzyme in question. ****************************************************************************** > Hello, > > A while back someone asked about success stories in rational > drug design. In that light, what does the group think of the Merck > groups article in *Science* 23:380-384 where they rationally designed > inhibitors of HIV protease? > > Martin J. Gallagher phone: (617) 432-1729 > Dept. of Neurobiology fax: (617) 734-7557 > Harvard Medical School E-mail: marty@ionchannel.med.harvard.edu Background information: here at Washington University we developed a 3D-QSAR - CoMFA model for 59 HIV-protease inhibitors (see J Med Chem 36:4152-4160 1993) - a model that was based on experimentally derived alignment rules (crystals of 7 inhibitors) and was tested for predictive power (36 compounds with different chemistry - but peptides as the other 59) and explanatory power (CoMFA fields were compared and interpreted in the light of binding site residues in immediate contact with the inhibitors). The work on predictive power was submitted to J Med Chem, and the one on explanatory power is to be printed in Drug Design and Discovery. .......... The non-peptide cyclic ureas were announced at the Gordon Conference in QSAR (August 1993) where Dr Eyermann gave a lecture (no activities, though). The four compounds with published activities were predicted by our model as follows (see the Science paper for #s): Cmpd Actual Predicted (both as IC50, micromolar) 1 0.63 0.132 2 0.30 0.140 3 0.22 0.23 4 0.036 0.061 .......... Comments regarding the drug design tactics used by the DuPont-Merck group (or how did they 'set forth' to get advantages in the HIV-protease front): structural knowledge of the free enzyme and the inhibitor-bound enzyme was ESSENTIAL for this study, because specific targets were aimed at: * atoms in the binding site which were important in the economy of binding which were used to define the * 3D pharmacophore (exact location of binding site atoms - which are then used as template for putative structures that can match this pattern), which was then used as a query in a * 3D database search (useful concept: has anyone done such a compound before? - ... or how close to our 3D pattern are already-made-cmpds ?) this proves many times to be of help, but users are aware that such a method would not suggest NEW compounds, and this is where the molecular modeler (or was it a medicinal chemist?) uses knowledge blended with imagination to come with the * "_initial_idea_ for a nonpetide inhibitor that includes a structural water mimic" (exact quote) - this suggests that someone in the group came with this suggestion, upon which the work was continued later on, the skeleton was refined to ensure * better complementarity with the 3D pharmacophore (e.g., two hydroxyls instead of one, to bind two aspartates in the catalytic site, and the urea instead of the keto to improve electrostatic negative pattern in the flaps region for better hydrogen bonding) .......... The Science paper proves that current concepts used in drug design are valid - but it is quite clear that a scientist (or a team of scientists) is needed, because this problem was not solved entirely by a computer. However, the use of computational methods was essential. ========================== Tudor-Ionel Oprea = Tel. (1-314) 935 4672 = tudor@wucmd.wustl.edu = =============================================================== I don't have the results of the previous survey, but a few examples. All of these are in the clinic (or were). Not in any particular order. 1. the Agouron thymidilate synthase inhibitors 2. the Abbott C2 symmetric HIV protease inhibitors 3. the Biocryst/Ciba/Cornell PNP inhibitors 4. the Dupont-Merck HIV protease inhibitors 5. the Merck carbonic anhydrase inhibitor (will be on the market this year!) Finally, our HIV protease inhibitor, VX-478, should be in the clinic later this year. Hope this helps. / Mark (markm@vpharm.com) Cheers, Dave __________________________________________________________________________ Dr. David A. Winkler Voice: 61-3-542-2244 Principal Research Scientist Fax: 61-3-543-8160 CSIRO Division of Chemicals and Polymers Private Bag 10 Clayton, Australia. "Life is what happens to you while you're making other plans" From DAREK@ichn.ch.pwr.wroc.pl Wed Jul 6 08:50:50 1994 Received: from sun1000.ci.pwr.wroc.pl for DAREK@ichn.ch.pwr.wroc.pl by www.ccl.net (8.6.9/930601.1506) id IAA25545; Wed, 6 Jul 1994 08:36:04 -0400 Received: from ichn.ch.pwr.wroc.pl by sun1000.ci.pwr.wroc.pl (5.0/SMI-SVR4) id AA20087; Wed, 6 Jul 1994 14:20:30 --100 Received: from ICHN_1/MAILQUEUE by ichn.ch.pwr.wroc.pl (Mercury 1.11); Wed, 6 Jul 94 14:23:27 +100 Received: from MAILQUEUE by ICHN_1 (Mercury 1.11); Wed, 6 Jul 94 14:22:48 +100 From: "Dariusz C.Bienko" Organization: Inst. of Inorg. Chem. PWr. To: chemistry@ccl.net Date: Wed, 6 Jul 1994 14:22:48 GMT+100 Subject: question X-Pmrqc: 1 Priority: normal X-Mailer: Pegasus Mail v3.1 (R1a) Message-Id: <3F0DDC7329@ichn.ch.pwr.wroc.pl> content-length: 0 Hi, Have you ever heard about some theoretical calculation on viruses? I think f.g. about some kind of geometry optimisations of their full molecular shapes or any other simulations related to viruses. Darek & Slawek From cletner@remcure.bmb.wright.edu Wed Jul 6 09:01:36 1994 Received: from remcure.bmb.wright.edu for cletner@remcure.bmb.wright.edu by www.ccl.net (8.6.9/930601.1506) id IAA25468; Wed, 6 Jul 1994 08:28:26 -0400 Received: by remcure.bmb.wright.edu (920330.SGI/921111.SGI.AUTO) for CHEMISTRY@ccl.net id AA15154; Wed, 6 Jul 94 08:18:44 -0700 Date: Wed, 6 Jul 1994 07:58:32 -0700 (PDT) From: Charles Letner Subject: Protonation state summary To: Computational Chemistry List Message-Id: Mime-Version: 1.0 Content-Type: TEXT/PLAIN; charset=US-ASCII Hello, I've gotten a number of usefull responses. As was expected the response turned to determining the pKa's of the AA's in the protein (I didn't specifically ask this question because I wanted to see if there where other answers not anticipated). Two other references from Bill Welsh's summary from May 23 are also usefull. Rob Setlik recommends: Bashford et al., (1993) Biochem 32, 8045. Yang et al., (1993) Protein 15, 252-265. Both of these are good papers. The Bashford et al. lists an ftp site ftp.scripps.edu in pub/electrostatics) to obtain the programs and data (Is this site possible a David Case piece of work, could be :) ). I've been there and there is an alpha version of a the program MEAD. I haven't unpacked this yet so I can't tell you much other than it exist. Thanks for the help. Untill next time, Chuck Charles Letner Wright State University Department of Biochemistry Dayton, OH 45435 e-mail: cletner@remcure.bmb.wright.edu ----------------- response summary ----------------------------------- From: "Dr. Walter J. Stevens" Quite a bit of work has been done on ionization states of amino acid side chains in proteins. See for example: M.K. Gilson, Proteins: Structure, Function and Genetics -15-, 266-282 (1993) J. Antosiewocz, J.A. McCammon, and M.K. Gilson J. Molec. Biol. -238-, 415-436 (1994) and references therein. This is a good review of the complexity of the problem you have addressed. -------------------------------------------------- Dr. Walter J. Stevens Center for Advanced Research in Biotechnology National Institute of Standards and Technology and University of Maryland Biotechnology Institute 9600 Gudelsky Drive Rockville, MD 20850 Phone: (301) 738-6264 FAX : (301) 738-6255 E-MAIL: walt@ibm1.carb.nist.gov -------------------------------------------------- From: "Jeffrey L. Nauss" I'm running into the same situation myself. The rule of thumb I am using is that if a protein is accessible to the solvent it is protonated as appropriate for the pH of the system under study. Fortunately, I am looking at systems at pH 7.0 or at low pH levels (3-4). Therefore, I feel I can still go for an all or nothing protonation for a given type of amino acid (i.e. all Glu will be protonated at the low pH). And, I do not have to worry about subtle variations in pKa due to local environments. As for salt bridges, the residues involved are charged. Residues at the active site present a different problem. There subtle pKa changes may have dramatic effects. Frankly, I am still a bit baffled as to how to handle them, especially one in my system of interest with a solvent accessible surface of only 1 Angstrom**2. I hope this rambling will be of some benefit to you. I am interested in your summary. Jeff Nauss **************************************************************************** * UU UU Jeffrey L. Nauss, PhD * * UU UU Director, Molecular Modeling Services * * UU UU Department of Chemistry * * UU UU CCCCCCC University of Cincinnati * * UU UU CCCCCCCC Cincinnati, OH 45221-0172 * * UUUU CC * * CC Telephone: 513-556-0148 Fax: 513-556-9239 * * CC * * CCCCCCCC e-mail: nauss@ucmod2.che.uc.edu * * CCCCCCC * **************************************************************************** From: "Jim Briggs, Ph.D., U of Houston, Chem. (713)743-3315" Chuck, I can't speak to your main question of the importance of having correct protonation states except that if you get one wrong in a critical area, you will likely see a large effect. I did want to respond to your secondary question of assigning protonation states to AAs in proteins. Using the approach that you suggest (i.e. the "null" model) should work most of the time. Assuming that residues that are on the surface are appropriately ionized depending on the pH and that internal residues are ionized if in "polar" environments (again, depending on pH). Obviously, you need to take a look at ALL histidines... Anyhow, there is an approach that was developed recently to predict ionization states depending on the pH, ionic strength, and electrostatic environment of each AA. The approach uses the electrostatics module of the UHBD (University of Houston Brownian Dynamics) program. The procedure and results are described in a recent paper: J. Antosiewicz, A. McCammon, M. Gilson J. Mol. Biol. 1994, 238, 415-436. In most cases, this approach does better than the "null" model as compared with experimentally determined ionization states. The UHBD manual can be downloaded for free from the anonymous ftp site: 129.7.8.16 under: pub/uhbd in DVI and PostScript forms. The code is available for a nominal fee to academic institutions and is distributed commercially through Molecular Simulations, Inc. I'm sure that a similar approach is available in conjunction with Barry Honig's DELPHI program... Jim Briggs JBriggs@uh.edu From: Soaring Bear Hi Chuck: I'm glad you posed that question because I've been wondering the same thing about drugs which contain amines which can equilibrate between both protonated & unprotenated states at physiological pH (as can Histidine). The grunt way of handling it would be to run the model each way seperatly but it would seem this is a common enough situation that modeling software ought to incorporate handling of this as a feature. I look foward to seeing the responses you get. bear * UU UU SOARING BEAR * * UU UU Computer Aided Drug Design * * UU UU A University of Arizona, New Pharmacy 404 * * UUUU AAA Tucson, AZ 85721 602-626-6133 * * AA AA where the sun shines * * AAAAAAA * * AA AA e-mail:bear@ellington.pharm.arizona.edu * From: Xiaoou Xiang Hi, Chuck: The only way to make certain about the protonation state is, of course, by getting hands wet with test tubes. The computational way to do that, not always reliable, is to locally minimize with the side chain under consideration in all protonation states, and then choose the one in which the side chain has the lowest energy of interaction with the local environment. In practice, one often only needs to ascertain the protonation state of residues in the region of interest in the protein, and assign arbitrary protonation states to other residues, assuming that the influence of (de)protonation does not propagate beyond 8-10 anstroems. Phil X. Xiang Brandeis University From: Paul Beroza People have been worried about this question, which usually falls under the topic, how do you determine an amino acid's pKa when it is bound to a protein? Here are a few references that I have at my fingertips. Paul (pberoza@ucsd.edu) --- Russel and Warshel, Journal of Molecular Biology, 185:389 (1985). "The Energetics of Ionized Groups in Bovine Pancreatic Trypsin Inhibitor" Bashford and Karplus, Biochemistry, 29: 10219 (1990), "pKa's of Ionizable Groups in Proteins: Atomic Detail from a Continuum Model" Beroza, et al., Proc. Natl. Acad. Sci., 88:5804 (1991), "Protonation of Interacting Residues in a Protein by a Monte Carlo Method: Application to Lysozyme and the Photosynthetic Reaction Center of Rhodobacter sphaeroides" Yang, et al., Proteins, 15:252 (1993), "On the Calculation of pKa's" in Proteins" From ADAMO@CHEMNA.DICHI.UNINA.IT Wed Jul 6 11:52:11 1994 Received: from CHEMNA.DICHI.UNINA.IT for ADAMO@CHEMNA.DICHI.UNINA.IT by www.ccl.net (8.6.9/930601.1506) id LAA28481; Wed, 6 Jul 1994 11:10:40 -0400 From: Received: from CHEMNA.DICHI.UNINA.IT by CHEMNA.DICHI.UNINA.IT (PMDF V4.2-11 #3559) id <01HEE6MFPM0G0006FR@CHEMNA.DICHI.UNINA.IT>; Wed, 6 Jul 1994 17:11:54 CET Date: Wed, 06 Jul 1994 17:11:53 +0100 (CET) Subject: G92/DFT for ALPHA/OSF: some compilation problem To: chemistry@ccl.net Message-id: <01HEE6MFQEYA0006FR@CHEMNA.DICHI.UNINA.IT> X-VMS-To: IN%"chemistry@ccl.net" X-VMS-Cc: ADAMO MIME-version: 1.0 Content-type: TEXT/PLAIN; CHARSET=US-ASCII Content-transfer-encoding: 7BIT Dear net-ters, I am trying to compile Gaussian G92/DFT v. G2 on ALPHA 300x machine. In the corresponding g92.make file there is the following option ESSLLIB= -ldxml which I suppose to correspond to a fortran library. The problem is that the compilation stops because we do not have this library. I loooked at the corresponding makefile for the IBM/RISC 6000 version and I found this: ESSLLIB= -lblas [other stuff] So I suppose that the dxml and blas library are the same. Am I right? But, now, where is it possible to find dxml (or blas) for ALPHA (OSF v. 1) ? Thank Ciao Carlo P.S. I tried, of course, to contact both Gaussian and Digital, but I received no answer ------------------------------------------------------------------------------- Carlo Adamo | tel. +39-81-5476504 Dipartimento di Chimica | fax +39-81-5527771 via Mezzocannone 4 | e-mail ADAMO@CHEMNA.DICHI.UNINA.IT I-80134 Napoli | Italy | ________________________________________________________________________________ From nash@chem.wisc.edu Wed Jul 6 13:46:19 1994 Received: from fozzie.chem.wisc.edu for nash@chem.wisc.edu by www.ccl.net (8.6.9/930601.1506) id MAA29613; Wed, 6 Jul 1994 12:15:55 -0400 Received: by fozzie.chem.wisc.edu; id AA12419; 5.57/42; Wed, 6 Jul 94 11:17:04 -0500 Message-Id: <9407061617.AA12419@fozzie.chem.wisc.edu> X-Sender: nash@fozzie.chem.wisc.edu Mime-Version: 1.0 Content-Type: text/plain; charset="us-ascii" Date: Wed, 6 Jul 1994 11:18:59 -0500 To: chemistry@ccl.net From: nash@chem.wisc.edu (John R. Nash) Subject: G92/DFT: spurious integrated density Hello all, I have been using G92/DFT to run density functional calculations on organometallics (using BLYP/LANL1DZ). On a number of occasions, G92/DFT gives me a "spurious integrated density" error while doing the SCF. Often, going to a finer grid (Int=FineGrid in the route card) solves the problem, but not always. The release notes that I have do not mention this error message -- I would be interested in the experiences of others in dealing with this problem. Thanks in advance, john nash -===-John R. Nash-==-nash@chem.wisc.edu-==-UW-Madison Chem. Dept-===- From cletner@remcure.bmb.wright.edu Wed Jul 6 13:51:35 1994 Received: from remcure.bmb.wright.edu for cletner@remcure.bmb.wright.edu by www.ccl.net (8.6.9/930601.1506) id MAA00324; Wed, 6 Jul 1994 12:57:21 -0400 Received: by remcure.bmb.wright.edu (920330.SGI/921111.SGI.AUTO) for CHEMISTRY@ccl.net id AA16176; Wed, 6 Jul 94 12:47:46 -0700 Date: Wed, 6 Jul 1994 12:42:14 -0700 (PDT) From: Charles Letner Subject: More on protonation states in proteins To: Computational Chemistry List Message-Id: Mime-Version: 1.0 Content-Type: TEXT/PLAIN; charset=US-ASCII Hello again, I need to update my summary from earlier this morning. Below is another reply I recieved. I must add one other reference I've come across today. For me, this has been one of those papers that sends my mind realing over the possbilities that exist. You might concider taking a look at this if your at all interested in protonation of proteins. Bashford & Gerwert (1992) L. Mol. Bio., 224, 473-486. Best regards, Chuck Charles Letner Wright State University Department of Biochemistry Dayton, OH 45435 e-mail: cletner@remcure.bmb.wright.edu ---------- Forwarded message ---------- From: Eberhard von Kitzing Dear Charles Letner, The following article might help: %0 Journal Article %A Russel, S. T. %A Warshel, Arieh %D 1985 %T Calculations of Electrostatic Energies in Proteins; The Energetics of Ionized Groups in Bovine Pancreatic Trypsin Inhibitor %J Journal of Molecular Biology %V 185 %P 389-404 %K electrostatic energy, proteins, intrinsic pK values, Bovine Pancreatic Trypsin Inhibitor, solvation energy, solvation energy, protein dipoles Langevin dipoles, force field design %0 Journal Article %A Reynolds, John C. L. %A Cooke, Kristi Forrest %A Northrup, Scott H. %D 1990 %T Electrostatic and Diffusional Dynamics in the Carbonic Anhydrase Active Site Channel %J Journal of Physical Chemistry %V 94 %P 985-991 %K diffusion, Brownian dynamics, pK values, electrostatic interaction ------------------------------------------------------------------------- Eberhard von Kitzing Max-Planck-Institut fuer Medizische Forschung Jahnstr. 29, D69120 Heidelberg, FRG Carl-Zuckmayer Str. 17, D69126 Heidelberg (privat) FAX : +49-6221-486 459 (work) Tel.: +49-6221-486 467 (work) Tel.: +49-6221-385 129 (home) internet: vkitzing@sunny.MPImF-Heidelberg.mpg.de From frederik@vega.acs.uci.edu Wed Jul 6 14:22:39 1994 Received: from vega.acs.uci.edu for frederik@vega.acs.uci.edu by www.ccl.net (8.6.9/930601.1506) id NAA00362; Wed, 6 Jul 1994 13:03:31 -0400 Received: from localhost.acs.uci.edu by vega.acs.uci.edu with SMTP id AA08652 (5.65c/IDA-1.4.4 for chemistry@ccl.net); Wed, 6 Jul 1994 10:03:54 -0700 To: ADAMO@chemna.dichi.unina.it Cc: chemistry@ccl.net Subject: Re: CCL:G92/DFT for ALPHA/OSF: some compilation problem In-Reply-To: Your message of Wed, 06 Jul 94 17:11:53 +0000. Date: Wed, 06 Jul 94 10:03:52 -0700 Message-Id: <8650.773514232@vega.acs.uci.edu> From: "Donald M. Frederick" > Dear net-ters, > I am trying to compile Gaussian G92/DFT v. G2 on ALPHA 300x machine. > In the corresponding g92.make file there is the following option > ESSLLIB= -ldxml > which I suppose to correspond to a fortran library. The problem is that the > compilation stops because we do not have this library. I loooked at the > corresponding makefile for the IBM/RISC 6000 version and I found this: > ESSLLIB= -lblas [other stuff] > So I suppose that the dxml and blas library are the same. Am I right? > But, now, where is it possible to find dxml (or blas) for ALPHA (OSF v. 1) ? > Thank > Ciao > Carlo > > > P.S. I tried, of course, to contact both Gaussian and Digital, but I received > no answer > > > > ------------------------------------------------------------------------------- > Carlo Adamo | tel. +39-81-5476504 > Dipartimento di Chimica | fax +39-81-5527771 > via Mezzocannone 4 | e-mail ADAMO@CHEMNA.DICHI.UNINA.IT > I-80134 Napoli | > Italy | > ________________________________________________________________________________ > > > > > ---Administrivia: This message is automatically appended by the mail exploder: > CHEMISTRY@ccl.net -- everyone | CHEMISTRY-REQUEST@ccl.net -- coordinator > MAILSERV@ccl.net: HELP CHEMISTRY | Gopher: www.ccl.net 73 > Anon. ftp www.ccl.net | CHEMISTRY-SEARCH@ccl.net -- archive search > http://www.ccl.net/chemistry.html | for info send: HELP SEARCH to MAILSERV "dxml" is the DEC Extended Mathematics Library and it contains BLAS (among other goodies, too) optimized for DEC alpha architecture. Your local DEC representative SHOULD be able to tell you all about dxml. As an alternative, You may want to just grab BLAS as Fortran source from the nearest netlib site to you and create your own BLAS library. The European site is: "netlib@nac.no". Just send e-mail to that address with the following one-line message body: send index from blas to obtain information about the BLAS package. Good luck. ------------------------------------------------------------------------ Donald Frederick | Office of Academic Computing frederik@uci.edu | University of California, Irvine asc@uci.edu | Irvine, CA 92717 (714) 725-3200 | FAX (714) 725-2069 ----------------------------------------------------------------------- From kb7@unix.york.ac.uk Wed Jul 6 14:35:46 1994 Received: from leeman.york.ac.uk for kb7@unix.york.ac.uk by www.ccl.net (8.6.9/930601.1506) id NAA00381; Wed, 6 Jul 1994 13:05:47 -0400 Received: from sgi8.york.ac.uk by leeman.york.ac.uk with SMTP (PP) id <10614-0@leeman.york.ac.uk>; Wed, 6 Jul 1994 18:01:40 +0100 Received: by sgi8.york.ac.uk (931110.SGI/920502.SGI) for @leeman.york.ac.uk:CHEMISTRY@ccl.net id AA09235; Wed, 6 Jul 94 19:51:09 +0100 Date: Wed, 6 Jul 1994 19:51:08 +0000 From: K Bryson Sender: K Bryson Reply-To: K Bryson Subject: MD & MC; Modelling of counterions effects in polyelectrolytes. To: CHEMISTRY@ccl.net Cc: K Bryson Message-Id: Mime-Version: 1.0 Content-Type: TEXT/PLAIN; CHARSET=US-ASCII Hi Folks, All this recent talk about electrostatic charges on protein surfaces and a previous posting about site-specific counter-ion binding around the pectic acid in plant cell walls has brought up a worry that I've had for some time now, I wonder what others think about this. This problem applies to all polyelectolyte modelling but I will use DNA to explain it since it's what I'm familiar with. In most of the modelling of DNA we place sodium counter-ions next to the -ve charged phosphate groups to make the system neutral. Now Debye-Manning theory determined that only around half the phosphates are neutralised at low ionic concentrations and that only when we get to very high salt concentrations do we get ( I vaguely remember ) around 0.7 of the phosphates neutralised by sodium ions, the rest sitting in a counter-ion atmosphere some distance away from the DNA. So the dilemna in my mind is that we model DNA with all the phosphates neutralised very locally as if we are modelling it in an extremely concentrated salt solution ( which it would denature in ). Would it not be better to neutralise half the phosphate groups locally with counterions and simulate a charged system ? Statistical mechanics would predict that the DNA would have between 0 and 24 ( for dodecamers ) ions bound onto it with different probabilities for each depending on salt concentration, so why does everyone model it with 24 counter-ions ? When at physiological conditions I believe it is most likely to have around 12 directly bound onto it ? This seems to apply to a lot of polyelectrolyte simulations ... full counter-ion neutralisation seems to be what is modelled, when electrolytic theory predicts that most polyelectrolytes are only partially neutralised by site-specific counter-ions in solution. What do others think ? Maybe I'm being pedantic ( or silly ! ) but the amount of counter-ions included in a simulation extensively effects the structure of the solute. Any better ways to include counterion concentration effects ? I suppose a Debye screening term dependant on concentration could be applied between all charged atoms separated by solvent in the system ... be computational due to the exponential term though ... is there a general concensus of belief on this problem ? Sorry about the large bandwidth. Kevin. ============================================================================= K.Bryson email: kb7@tower.york.ac.uk Biophysics Group Tel : +44 904 430000 Extn. 2236 Physics Department Fax : +44 904 432214 University of York Heslington "Molecular modelling of DNA and its YORK, UK interaction with small molecules." YO1 5DD ============================================================================= From brian@bert.chem.wsu.edu Wed Jul 6 14:48:44 1994 Received: from serval.net.wsu.edu for brian@bert.chem.wsu.edu by www.ccl.net (8.6.9/930601.1506) id MAA00334; Wed, 6 Jul 1994 12:59:12 -0400 Received: by serval.net.wsu.edu; id AA17582; Wed, 6 Jul 1994 10:00:14 -0700 Received: by bert.chem.wsu.edu (AIX 3.2/UCB 5.64/4.03) id AA21400; Wed, 6 Jul 1994 10:00:43 -0700 From: brian@bert.chem.wsu.edu (Brian W. Beck) Message-Id: <9407061700.AA21400@bert.chem.wsu.edu> Subject: Re: CCL:question To: DAREK@ichn.ch.pwr.wroc.pl (Dariusz C.Bienko) Date: Wed, 6 Jul 1994 10:00:42 -0800 (PDT) Cc: chemistry@ccl.net In-Reply-To: <3F0DDC7329@ichn.ch.pwr.wroc.pl> from "Dariusz C.Bienko" at Jul 6, 94 02:22:48 pm X-Mailer: ELM [version 2.4 PL13] Mime-Version: 1.0 Content-Type: text/plain; charset=US-ASCII Content-Transfer-Encoding: 7bit Content-Length: 3009 Dariusz C.Bienko wrote: : : Hi, : Have you ever heard about some theoretical calculation on : viruses? I think f.g. about some kind of geometry optimisations : of their full molecular shapes or any other simulations : related to viruses. : Darek & Slawek : Wade & McCammon did some work on HRV in 1992. I did a journal club presentation on these articles. You might be able to use them to boot-strap yourself to the latest stuff. What follows is the references for the above articles: (it's a two part article). Author: Wade-R-C. McCammon-J-A. Title: Binding of an antiviral agent to a sensitive and a resistant human rhinovirus. Computer simulation studies with sampling of amino acid side-chain conformations. II. Calculation of free-energy differences by thermodynamic integration. Source: J-Mol-Biol. 1992 Jun 5. 225(3). P 697-712. Journal Title: JOURNAL-OF-MOLECULAR-BIOLOGY Subject Major: ANTIVIRAL-AGENTS: me. OXAZOLES: me. RHINOVIRUS: me. VIRAL-PROTEINS: me. Subject Minor: ANTIVIRAL-AGENTS: ch. COMPUTER-SIMULATION. CRYSTALLOGRAPHY. DRUG-RESISTANCE-MICROBIAL. LEUCINE: ch. MODELS-MOLECULAR. MOTION. OXAZOLES: ch. RHINOVIRUS: ch. STRUCTURE-ACTIVITY-RELATIONSHIP. SUPPORT-NON-US-GOVT. SUPPORT-US-GOVT-NON-PHS. THERMODYNAMICS. VALINE: ch. VIRAL-PROTEINS: ch. WATER. Author: Wade-R-C. McCammon-J-A. Title: Binding of an antiviral agent to a sensitive and a resistant human rhinovirus. Computer simulation studies with sampling of amino acid side-chain conformation. I. Mapping the rotamers of residue 188 of viral protein 1. Source: J-Mol-Biol. 1992 Jun 5. 225(3). P 679-96. Journal Title: JOURNAL-OF-MOLECULAR-BIOLOGY Subject Major: ANTIVIRAL-AGENTS: me. OXAZOLES: me. RHINOVIRUS: me. VIRAL-PROTEINS: me. Subject Minor: ANTIVIRAL-AGENTS: ch. COMPUTER-SIMULATION. CRYSTALLOGRAPHY. DRUG-RESISTANCE-MICROBIAL. LEUCINE: ch. MOLECULAR-STRUCTURE. MOTION. OXAZOLES: ch. PROTEIN-CONFORMATION. SUPPORT-NON-US-GOVT. SUPPORT-US-GOVT-NON-PHS. THERMODYNAMICS. VALINE: ch. VIRAL-PROTEINS: ch. -Brian -- ============================================================================= | .---------.| Brian W. Beck | E-mail Addresses: | |/\ | ||--------------------| INTERNET brian@bert.chem.wsu.edu | || \\ WSU || Biochem/Biophysics | BITNET F0388913@WSUVMS1 | |\ - *|| WSU , 261 Fulmer | DECNET JAGUAR::F0388913 | | | || Pullman, WA | VOICE (509) 335-4083 | | \___________|| 99164-4660 | FAX (509) 335-9688 | ============================================================================= From chemdcl3@emrycc.cc.emory.edu Wed Jul 6 15:50:56 1994 Received: from emoryu1.cc.emory.edu for chemdcl3@emrycc.cc.emory.edu by www.ccl.net (8.6.9/930601.1506) id PAA03830; Wed, 6 Jul 1994 15:43:35 -0400 Received: from emrycc.cc.emory.edu by emoryu1.cc.emory.edu (5.65/Emory_cc.3.5.2) via SMTP id AA04531 ; Wed, 6 Jul 94 15:44:35 -0400 Message-Id: <9407061944.AA04531@emoryu1.cc.emory.edu> Date: 6 Jul 94 15:42:00 EST From: "DR. LIOTTA" Subject: CCL: re:rRNA summary To: "chemistry" Thank you to the various people who responded to the following message: >We would like to model the secondary structure of ribosomal >RNA and would like to contact anybody who has done similar >work or who can lead us to useful references. Are there any >crystollographic structures of rRNA available? Here is a summary of the responses: 1] "I have mostly used Michael Zukers MFold software to predict RNA secondary structure." ... and "Here is one paper:" Baldridge, G.D.; Dalton, M.W.; Fallon, A.M.; Is higher order Structure Conserved in Eukaryotic Ribosomal DNA Intergenic spacers?, Journal of Molecular Evolution, vol 35, (1992) Mark Dalton mwd@cray.com 2] "We are doing NMR spectroscopy of ions in ribosomal solutions, and would be interested in any information you get from the net about crystal structures etc.. of rRNA. A few articles that deal with ribosomal structure in general are: Crichton et al. 1977. PNAS 74:5547 Tardieu and Vachette 1982. EMBO J. 1?:35 Wittmann 1983. Ann. Rev. Biochem. 52:35" Harry J. Guttman guttman@poly.nn.wisc.edu 3] "Perhaps the following articles will be of interest: (a) Malhotra, Arun; Gabb, H.A; Harvey, S.C.; Modelling large nucleic -acids; Current Opinion in Structural Biology; vol 3 (2) p241-246 (1993)" (b) Malhotra, Arun; Tan, R.K.-Z.; Harvey, S.C.; Modelling large RNAs and ribonucleoprotein particles using molecular mechanics techniques, Biophysical Journal, vol 66; p1777-1795 (1994) Eberhard von Kitzing vkitzing@sunny.mpimf-Heidelberg.mpg.de 4] "There is extensive noncrystollographic work from the labs of Woese, Noller and Gutell. A quick medline search should turn these up. There is reasonable literature on ribosomal structure, by chemical cross- linking (labs of Wool and Wittman), electron micrography and maybe neutron scattering. There are probably some clues there. I doubt if there are crystals of isolated rRNAs, but if there are they should be in nucleic acids database (NDB) at Rutgers." Toni Kazic toni@athe.wustl.edu 5] "To the best of my knowledge there are two items in the PDB that might interest you: (a) theoretical model of 5s rRNA and (b) NMR structures of rRNA. Here are the headers for your information: HEADER RIBONUCLEIC ACID COMPND 5s RIBOSOMAL RNA (HELIX I) (NMR, 6 STRUCTURES) SOURCE (ESCHERICHIA COLI) EXPDTA NMR AUTHOR S.WHITE, P.MOORE REVDAT 31-JAN-94 1ELH 0 JRNL AUTH S.A.WHITE,M.NILGES,A.HUANG,A.T.BRUNGER,P.B.MOORE JRNL TITL NMR ANALYSIS OF HELIX I FROM THE 5s RNA OF JRNL TITL 2 ESCHERICHIA COLI JRNL REF BIOCHEMISTRY V. 31 1610 1992 JRNL REFN ASTM BICHAW US ISSN 0006-2960 033 HEADER RIBONUCLEIC ACID COMPND 5 s RIBOSOMAL RNA (THEORETICAL MODEL) SOURCE (XENOPUS LAEVIS) OOCYTES EXPDTA THEORETICAL MODEL AUTHOR E.WESTHOF, P.ROMBY, C.EHRESMANN REVDAT 2 31-JAN-94 1RRNA 1 REMARK REVDAT 1 31-OCT-93 1RRN 0 JRNL AUTH E.WESTHOF, P.ROMBY, P.J. ROMANUIK, J.-*P.EBEL, JRNL AUTH C.EHRESMANN, B.EHRESMANN JRNL TITL COMPUTER MODELLING FROM SOLUTION DATA OF SPINACH JRNL TITL 2 CHLOROPLAST AND OF XENOPUS LAEVIS SOMATIC AND JRNL TITL 3 OOCYTE 5 S $R/RNA$S JRNL REF J.MOL.BIOL V. 207 417 1989 JRNL REFN ASTM JMOBAK UK ISSN 0022-2836 070" C.S. Ramen raman@launchpad.unc.edu 6] Peter Reinert also gave reference 3 (b) "For obtaining the software contact tan@neptune.cmc.uab.edu" Peter Reinert reinert@VAX.MPIZ-KOELN.MPG.d400.de These were very helpful, Veronica Cornel chemdcl3@emrycc.cc.emory.edu From billg@SCGROUP.BARRNET.NET Wed Jul 6 17:51:01 1994 Received: from mail.barrnet.net for billg@SCGROUP.BARRNET.NET by www.ccl.net (8.6.9/930601.1506) id QAA04981; Wed, 6 Jul 1994 16:51:48 -0400 Received: from fujitsuI.fai.com by mail.barrnet.net (5.67/1.37) id AA22855; Wed, 6 Jul 94 13:52:48 -0700 Received: from scg.scg.fai.com by fujitsu1.fujitsu.com (4.1/SMI-4.1) id AA17279; Wed, 6 Jul 94 13:52:29 PDT Received: by scg.scg.fai.com (4.1/SMI-4.1) id AA03233; Wed, 6 Jul 94 13:53:07 PDT Date: Wed, 6 Jul 94 13:53:07 PDT From: billg@scg.fujitsu.com (Marketing) Message-Id: <9407062053.AA03233@scg.scg.fai.com> To: chemistry@ccl.net Subject: software:environment Dear Netters, Has anyone heard of any of the following codes: PRZM, GLEAMS, EXAMS, and EPIC They are presumably used for environmental modeling to assess the fate of pollutants in the environment. I am curious as to the models that underlie these codes. For example, what kinetic, thermodynamic, and transport models are used to determine how a compound partitions between the water, ground, and atmosphere? On a related note, what is the level of maturity of the field of environmental modeling (probably macroscopic) versus molecular modeling (microscopic)? Finally, where can one obtain these codes and on which platforms do they run? Thanks in advance for your help. Bill ********************************************************************* * William A. Glauser, Ph.D. | Internet: billg@scg.fai.com * * Computational Chemist | Voice: (610) 436-8125 * * SuperComputer Group | FAX: (610) 430-1526 * * Fujitsu America, Inc. | * ********************************************************************* From mainz@chem.columbia.edu Wed Jul 6 18:11:27 1994 Received: from amazon.chem.columbia.edu for mainz@chem.columbia.edu by www.ccl.net (8.6.9/930601.1506) id QAA05042; Wed, 6 Jul 1994 16:54:43 -0400 Received: by amazon.chem.columbia.edu id AA21440 (5.65c/IDA-1.4.4 for CHEMISTRY@ccl.net); Wed, 6 Jul 1994 16:56:09 -0400 Date: Wed, 6 Jul 1994 16:56:08 -0400 (EDT) From: Daniel Mainz Subject: G92: charge-fitting and polarizabilities To: CHEMISTRY@ccl.net Message-Id: Mime-Version: 1.0 Content-Type: TEXT/PLAIN; charset=US-ASCII Greetings, Gaussian-ophiles. We are attempting to use Gaussian 92 to obtain charges to use in a MD simulation of formaldehyde. We are running Gaussian on an IBM RISC-station. We are having trouble with the population=(chelpg,dipole) option with the 6-311G** basis. For some reason, the chelpg routine thinks that the dipole moment in the z-direction is 13.94D, rather than the 2.77D it should be. Furthermore, chelpg assigns different charges to the two hydrogen atoms of formaldehyde. A similar problem occurs when we use population=(chelpg), again with the 6-311G** basis: the molecule develops a net dipole along the y-axis, in violation of the molecular symmetry. We have noticed that the 6-31G** basis does not suffer from this problem, and gives the expected result. Nevertheless, I would like to use a triple-zeta basis set rather than a double-zeta basis. The same type of problem occurs at the MP2 level of theory, and also using the scf=(tight,direct) keyword. Have others out there seen this behavior, and have quick fixes that we are overlooking? Below are the input file and parts of the output file. Please direct personal replies to bader@chem.columbia.edu. Thank you. Joel Bader and Daniel Mainz, Dept. of Chemistry, Columbia University Input file: --------------------------------------------- #RHF 6-311G** population=(chelpg,dipole) scf=(direct) test formaldehyde experimental geometry 0 1 O C 1 CO H 2 CH 1 AHCO H 2 CH 1 AHCO 3 AD CO 1.203 CH 1.099 AHCO 121.75 AD 180. Relevant parts of the output file: ---------------------------------------------- Dipole moment (Debye): /*from the wave function*/ X= .0000 Y= .0000 Z= -2.7715 Tot= 2.7715 ^ makes sense. .... Breneman (CHELPG) radii used for charge fitting Generate Potential Derived Charges using the Brenneman model, NDens= 1. Grid spacing= .300 Box extension= 2.800 NStep X,Y,Z= 19 25 25 Total possible points= 11875 Number of Points to Fit= 4808 Charge= .00000 Dipole= .0000 -.2127 -13.9414 Tot= 13.9431 1 1 O -1.798223 ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ 2 C .519942 What's going on here? 3 H .615452 4 H .662829 From lohrenz@zinc.chem.ucalgary.ca Wed Jul 6 18:50:58 1994 Received: from zinc.chem.ucalgary.ca for lohrenz@zinc.chem.ucalgary.ca by www.ccl.net (8.6.9/930601.1506) id SAA05792; Wed, 6 Jul 1994 18:45:38 -0400 From: Received: by zinc.chem.ucalgary.ca (AIX 3.2/UCB 5.64/4.03) id AA21178; Wed, 6 Jul 1994 16:24:17 -0600 Date: Wed, 6 Jul 1994 16:24:17 -0600 Message-Id: <9407062224.AA21178@zinc.chem.ucalgary.ca> To: chemistry@ccl.net, nash@bert.chem.wisc.edu Subject: Re: CCL:G92/DFT: spurious integrated density Hi John I while ago I had the same problem. The solution is: try SCF=NoVarInt. Even better: Try to get a newer release. M. Frisch actually told me, that they are aware of the problem and that there will be a new release. See also in my summary (must have been in July) in CCL. Good luck, John Lohrenz From C1790@SLVAXA.UMSL.EDU Wed Jul 6 19:50:57 1994 Received: from SLVAXA for C1790@SLVAXA.UMSL.EDU by www.ccl.net (8.6.9/930601.1506) id TAA06100; Wed, 6 Jul 1994 19:31:51 -0400 Received: from SLVAXA.UMSL.EDU by SLVAXA.UMSL.EDU (PMDF V4.2-11 #2503) id <01HEE9FY5SYU8ZDVPS@SLVAXA.UMSL.EDU>; Wed, 6 Jul 1994 18:32:33 CST Date: Wed, 06 Jul 1994 18:32:33 -0600 (CST) From: BILL WELSH Subject: Question about Clark Still's Generalized Born Solvation Model To: chemistry@ccl.net Message-id: <01HEE9FY5SYW8ZDVPS@SLVAXA.UMSL.EDU> X-VMS-To: in%"chemistry@ccl.net" MIME-version: 1.0 Content-type: TEXT/PLAIN; CHARSET=US-ASCII Content-transfer-encoding: 7BIT Dear Netters, Two questions about the GB solvation Model available in Macromodel: 1. The procedure uses the SA ("Surface Area") as a parameter in calculating the solvation free energy. What algorithm does Macromodel use to calculate this SA term for a given molecule. Is this procedure published somewhere in a detailed manner? 2. I seem to remember that Clark Still, et al., published an article in JACS or in the J. Comput. Chem. which describes the Generalized Born method. Can someone cite this (these) references for me? Thanks for any feedback .... Bill Welsh Dept. of Chemistry Univ. of Missouri-St. Louis From C1790@SLVAXA.UMSL.EDU Wed Jul 6 20:05:25 1994 Received: from SLVAXA for C1790@SLVAXA.UMSL.EDU by www.ccl.net (8.6.9/930601.1506) id TAA06148; Wed, 6 Jul 1994 19:40:20 -0400 Received: from SLVAXA.UMSL.EDU by SLVAXA.UMSL.EDU (PMDF V4.2-11 #2503) id <01HEE9QLP8VG8ZDVPS@SLVAXA.UMSL.EDU>; Wed, 6 Jul 1994 18:41:08 CST Date: Wed, 06 Jul 1994 18:41:08 -0600 (CST) From: BILL WELSH Subject: Calculating residue-by-residue binding energies To: chemistry@ccl.net Message-id: <01HEE9QLP8VI8ZDVPS@SLVAXA.UMSL.EDU> X-VMS-To: in%"chemistry@ccl.net" MIME-version: 1.0 Content-type: TEXT/PLAIN; CHARSET=US-ASCII Content-transfer-encoding: 7BIT Dear Netters, I want to calculate the binding energy of a protein on a surface of glass. I have a model glass surface constructed, and the protein-glass binding energy is pretty straightforward to calculate. However, I want to calculate (estimate) the binding energy of the protein to glass on a residue-by-residue basis. In other words, I want to identify energetically which residues are functionally most important for the binding affinity of the protein to the glass. Any suggestions are much appreciated. From recent conversations, I gather that interest in this question is widespread. So I will post a summary of responses if I receive several hits. thanks much ... Bill Welsh Dept. of Chemistry Univ. of Missouri-St. Louis From ravishan@swan.wcc.wesleyan.edu Wed Jul 6 21:50:58 1994 Received: from swan.wcc.wesleyan.edu for ravishan@swan.wcc.wesleyan.edu by www.ccl.net (8.6.9/930601.1506) id VAA06615; Wed, 6 Jul 1994 21:05:49 -0400 Received: by swan.wcc.wesleyan.edu (AIX 3.2/UCB 5.64/4.03) id AA15036; Wed, 6 Jul 1994 21:11:09 -0400 Date: Wed, 6 Jul 1994 21:11:09 -0400 Message-Id: <9407070111.AA15036@swan.wcc.wesleyan.edu> From: "G. Ravishanker" To: kb7@unix.york.ac.uk Cc: CHEMISTRY@ccl.net, kb7@unix.york.ac.uk In-Reply-To: (message from K Bryson on Wed, 06 Jul 1994 19:51:08 +0000) Subject: Re: CCL:MD & MC; Modelling of counterions effects in polyelectrolytes. Kevin I would like to comment on the MD simulations of the DNA. We have spent the past six years trying various methods to simulate the DNA with and without counterions. As you correctly point out, it is a serious headache, especially while trying to do a nanosecond level MD on DNA. Here are some of our observations (We use WESDYN, a derivative of GROMOS, and the force field used is GROMOS 86 with SPC water. All discussions here refer to the dodecamer sequence CGCGAATTCGCG): 1. Our goal is to simulate a "dilute aqueous solution" of DNA. As a result, we do not apply solute-solute boundary conditions - one should configure the box/cutoff correctly to avoid some of the artifacts of arising from this model. 2. In order for 1 to work correctly, we cannot have the counterions roam freely, so they are confined to a region around the surface of the DNA using a harmonic restraint. (In some sense, if we did this to 75% of the counterions, we will be consistent with the Manning counterion-condensation model!) 3. With 1 and 2, the DNA typically looks "OK" (by conventional convergence criteria) for the first 150ps or so, and then all sorts of things happen. Basically, the harmonic restraint shifts the ions to be between two Phosphate groups and the DNA begins to overwind itself etc. 4. So, we decided to skip the ions altogether. (We, in parallel, began a NaCl solution simulation to understand the effects of various protocols on the outcome of the simulation and found really strange things, such as the like-ions showing an enormous peak in g(R) at whatever the non-bonded cutoff is. This is likely to happen in the DNA simulation also. This work was done by Pascal Auffinger and is being currently written up) We scaled all Phosphate group charges down to -.25 by simply multiplying the original charges by .25. (CHARMM has a scaled charge model, where the total Phosphate group charge adds up to -.25, but the individual atomic charges are still very high) 5. We have a nanosecond MD with this model, showing very stable DNA structure. A preliminary communication of this appeared in JACS, vol. 116, 4461-4462 (Authors Kevin McConnell et.al). A detailed paper is under preparation. We have had reasonable success with this model for various other sequences ( as measured by the DNA structural stability, and calculated NMR properties compared against measured properties) also. We are currently rethinking the whole protocol and we will soon be getting back to the explicit counterions in some form or the other. It also is a fact that for non-canonical B-DNA, the net charges on phosphates need not be -.24 (see the paragraph below), so anyone wanting to model Manning's theory, should be constantly readjusting the fractional charges on the phosphates (may not be much of a change!!!!). I offer my sincere apologies, if the following paragraph is a restatement of a well-known thing and therefore a waste of bandwidth: The net charge of -.25 on phosphate groups is valid ONLY for B-DNA at 298 K. The general condensation formula is: f = 1./ (N * Zeta) Zeta > 1./N = 1. Zeta < 1./N Here f in the uncompensated charge fraction on the phosphate, N is the valence of the counterion and Zeta is a dimensionless measure of polyion charge density. Zeta = q**2 / (epsilon*k*T*b) q is the protonic charge, epsilon, the dielectric constant of solvent, k , the Boltozmann constant, T, the temperature and b is the average linear charge spacing between the phosphates along the helical axis. For an aqueous solution of canonical B-DNA at 298 K, the fractional charge is -.24 for Na+ and -.12 for Mg2+. Ravi **************************************************************************** * Ganesan Ravishanker Ph: (203) 344-8544 Ext. 3110 * * Coordinator of Scientific Computing, Fax:(203) 344-7960 * * Adjunct Associate Professor(Dept. of Chem.) * * Wesleyan University e-mail:ravishan@swan.wcc.wesleyan.edu * * Middletown, CT 06459. * ****************************************************************************