From UDIM018%FRORS31.BITNET@phem3.acs.ohio-state.edu Mon Jun 28 04:40:58 1993 Date: Mon, 28 Jun 1993 08:40:58 -0400 (EDT) From: UDIM018%FRORS31.BITNET@phem3.acs.ohio-state.edu Subject: Refereeing Semiempirical Papers To: chemistry@ccl.net Message-Id: <01GZWAUOZYG29H09BO@phem3.acs.ohio-state.edu> E. M. EVLETH Dynamique des Interactions Moleculaires Universite Pierre et Marie Curie 4 Place Jussieu, Tour 22, Paris 75005 33-1-44-27-42-08 (work), 33 = France; 1 = Paris 33-1-45-48-67-20 (home) FAX 33-1-44-27-41-17 (lab);44-27-38-66(University) e-mail UDIM018 at FRORS31.BITNET Henry Rzepa's comments on refereeing papers and reproducible results allows me to call attention to some of the earlier versions of AMPAC. I rejected an article several year ago which claimed to have done AM1 calculations on sulfur containing structures using a version of AMPAC dated before that that parameterization had done. Moreover, the article containing the AM1 parameterizations had not yet been published. The authors had already published several previous papers using "AM1" parameter- zations. Neither the authors nor the referees could check the sulfur compound calculations with the literature. I told the authors to check with Dewar. They did and it turned out that earlier versions of AMPAC would grab MNDO sulfur parameters and do "the calculation". The authors had to call attention to the fact that their earlier papers used "mixed AM1-MNDO" parameters. Later versions of AMPAC have been corrected and do not mix parameters. We have cited in some of own published work the inability of reproducing the semiempirical calculations of others who have programmed their own version of a particular semiempirical parameterization. Now that SAM1 tables are published at least one can check one's results against those generated by AMPAC 4.5 and upcoming versions of that program. The debate of whether one can alternatively program SAM1 into one's own program based on published information will go on for while. But based on past experience this will generate some faulted programs. Those who use them will have to continually check their results with the original paper. Past experience also indicates that all will not and referees will have to run check calculations to verify results in submitted papers. Not all referees will. So let the reader beware. The advantage of using a commercial program are net. If that program is wrong, one has somebody else to blame. That and the down time in writing one's own program is worth the price of a program. From UDIM018%FRORS31.BITNET@phem3.acs.ohio-state.edu Mon Jun 28 06:36:21 1993 Date: Mon, 28 Jun 1993 10:36:21 -0400 (EDT) From: UDIM018%FRORS31.BITNET@phem3.acs.ohio-state.edu Subject: Reference clarification on SAM1 To: chemistry@ccl.net Message-Id: <01GZWF54TD0I9H014V@phem3.acs.ohio-state.edu> E. M. EVLETH Dynamique des Interactions Moleculaires Universite Pierre et Marie Curie 4 Place Jussieu, Tour 22, Paris 75005 33-1-44-27-42-08 (work), 33 = France; 1 = Paris 33-1-45-48-67-20 (home) FAX 33-1-44-27-41-17 (lab);44-27-38-66(University) e-mail UDIM018 at FRORS31.BITNET Andy Holder referenced a thesis by James Ruiz U. of Austin, 1990. Dissertation Abstracts Int. Vol 50 p4019B (1990) gives an abstract of the thesis dated 1989. This thesis abstract does not specifically mention "SAM1", it does cite AM1 and alludes to a new method as applied to hydrocarbons. This thesis is available under order number DA9005659 from the service (usually a microprinted edition) phone in orders through 800-343-5299, ext 781 (Canada); 800-521-3042 (USA). One convenience DA Service takes credit cards, which avoids having to pay outrageous bank charges to secure checks payable in $ outside the USA. In my priprint copy of the paper by Dewar, Jie, and Yu (kindly sent to me by Andy Holder, the published Tetrahedron article has not yet arrived in Paris) there are no tables of SAM1 parameters for the C,H,N,O atoms. one suspects that these two above literature sources are insufficient to permit the independent investigator to reproduce SAM1 calculations. Personally, we run AMPAC 4.5 so my ox is not gored. It is a good program and worth the money. Many who do semiempirical calculations accept they are voo-doo quantum mechanics and one has to go to the right witchdoctor. I still cry a little for my 3rd world colleagues in not being able to join the club. From DSMITH@uoft02.utoledo.edu Mon Jun 28 04:08:24 1993 Date: Mon, 28 Jun 1993 09:08:24 -0500 (EST) From: "DR. DOUGLAS A. SMITH, UNIVERSITY OF TOLEDO" Subject: Re: full disclosure To: chemistry@ccl.net Message-Id: <01GZWM2DFMBM000SKD@UOFT02.UTOLEDO.EDU> Alain St-Amant recently replied to a statement in my posting: >I'll assume that Dr. Smith is referring to the specific algorithms that are >implemented that make the program more efficient but do not affect the final >results. In which case, I might agree. Thank you - this is what I mean but upon rereading my posting I was not clear. >Of course, I couldn't disagree more if he is referring to some development >in the methodology that actually affects the final results in any way. I agree with you! >The point that interests me however, is the question of software copyrights >and patents to which Dr. Smith alludes. I have been trying to get a feel >for what can be copyrighted and patented and I get a different answer from >everyone. Can only specific code be copyrighted or can the structure and >algorithms be copyrighted as well? How 'modified' should code be before >it can be called legally (and ethically if anyone is interested in expressing >an opinion) a new program? Or is it simply forbidden for code to "evolve" >into a new program? And David States follow up with: >The issues surrounding software patents are extremely complex and >precedents are often conflicting. There is a USENET newsgroup devoted >soley to this subject (comp.patents). > >A copyright protects the reproduction of a particular form of a piece >of work. The structure of an alogrithm would, therefore, not generally >be considered copyrightable. On the otherhand, simply changing the >variable names, or even disassembling object code and incorporating the >resulting sources into your own work is still basically reproducing the >previous representation of the work and therefore is covered by >copyright. This is a description of the legal copyright problem known as derivative work. Technically, if you change the spelling of your variables you have a new work which can be copyrighted. However, if this is (to the examiner at the copyright office) substantially the same as another, earlier work and is derived primarily from that earlier work, then it is a derivative. A derivative (I believe) is only able to be copyright by the author of the original work or his/her assignees, not by a third party because the work was not the work of that third party. >The structure of an algorithm may be patentable, and if a patent has >been issued you may be bound by it even if you independently derive the >algorithm or implement the code. Well known example is the RSA public >key encryption. Quite true- and other, less obvious software/algorithm patents are possible as well. For example, MOPAC 93 is protectted by a copyright. Had it been relatively new methods, or old methods put together in new and novel ways that lead to capabilities that are either 1) new and novel or 2) significant improvements over current technology, then Jimmie Stewart could have also applied for a patent. I spoke with a lawyer about this recently and was told that there are over 1200 software patents currently issued, most of those in the past year or two. Furthermore, the patent examiners tend not to be experts in software so have a hard time with determining the validity of the patent application claims (in his humble opinion). The rules are just now being operationally determined for software patents. On another, related topic, Mark Thompson wrote: >Do I read this statement correctly? It has been 8 years since the >original AM1 reference. I presume these "special corrections" >were known at the time the method was coded? This seems like >an inordinately long time to wait for a complete description of >the method. I will give you the benefit of the doubt and assume >I read this incorrectly!! Everyone should note that in the most recent issue of J. Am. Chem. Soc. (number 12, I believe - another professor has borrowed my copy) Michael Dewar and Jimmie Stewart appear as co-authors! There is a correction to the original AM1 paper of Dewar, Zoebisch, Healy and Stewart, published in 1985! The correction is to the paper, not to any problems in the program. In another posting, David States puts forth some interesting and reasonable guidelines for reproducibility and publication. I have to worry about the following one, though: >4) Who paid for it? > > This is the crux of the data issue, but the same reasoning > can be applied to code development. If something is the > result of work performed under a publically funded reserach > grant or award from a charitable foundation, it seems like the > fruits of that research ought to be fully accessible to the > academic community. Diverting the rewards of work funded by > public moneys to obtain substantial personal gain is hard to > defend. While this issue in the corporate world has been resolved long ago, in the academic world it is often less clear. In particular, I do not recall ever seeing a statement in my NIH or NSF applications or in any awards from those institutions that I have signed away rights to own the development rights, or even that the work is not my intellectual property. In fact, my University (and most others, I am sure) would not accept the grant if NIH owned the intellectual property rights - the University typically owns that. Enough for now. Doug Douglas A. Smith Assistant Professor of Chemistry The University of Toledo Toledo, OH 43606-3390 voice 419-537-2116 fax 419-537-4033 email dsmith@uoft02.utoledo.edu From yverband@is1.bfu.vub.ac.be Mon Jun 28 10:49:07 1993 From: yverband@is1.bfu.vub.ac.be (Verbandt Yves) Message-Id: <9306281449.AA00101@is3e.vub.ac.be> Subject: biphenyl optical data To: chemistry@ccl.net Date: Mon, 28 Jun 93 16:49:07 MDT Dear networkers, can anyone give me some references or data on the optical properties of biphenyl in the different phases and in different solutions. I am mostly interested in the visible wavelength range. I want to thank those who helped me last week with the geometrical data on the same compound. Thanks in advance, Yves Verbandt ================================================================ Yves Verbandt tel. 32-2-641.34.54 Brussels Free University fax. 32-2-641.34.50 Applied Physics Departement email yverband@vub.ac.be Pleinlaan 2 B-1050 Brussel BELGIUM ================================================================ From ADAMO@CHEMNA.DICHI.UNINA.IT Mon Jun 28 17:27:52 1993 Date: Mon, 28 Jun 1993 16:27:52 +0100 (CET) From: ADAMO@CHEMNA.DICHI.UNINA.IT Subject: SAM1 and AM1 references To: chemistry@ccl.net Message-Id: <01GZX2E9A7AQ00008D@CHEMNA.DICHI.UNINA.IT> Dear netters, we want add some comments on the debats entitled "SAM1 reference". 1. It is about 1 year that AMPAC realese 4.0 with SAM1 parametrization is commercially available. This means about 1 year before any clafiricatory (?) paper appeared. 2. Contrary to MOPAC and earlier version of AMAPC (up to 2.1), AMPAC version 4.x is in a "black box" format. That is, only executable files are avaible to the user. So no check is possible on the parametrization. 3. It seems to us, that the policy of prof. Holder is (and perhaps will be) to distribute only binary code of the program. In this connection we had an e-mail talk with prof. Holder that we add (see below). Moreover, we should like to know your opinion on the actual trend in commercializing computational packages without source codes. Does this trend encourage the development of science? And also: up to what limit a computational package can be considered as a product of a single research group? Vincenzo Barone Carlo Adamo ------------------------------------------------------------------------------- Vincenzo Barone & 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 | ________________________________________________________________________________ ------------------------------------------------------------------------------- Dear prof. Holder, I have read about the 4.0 version of AMPAC. I am very interested in this new version, so I should like to know more about the new features and the machine requirements (hardware and software) for the graphical interface.. Actually I have a IBM/RS 6000 machine, several IBM-PC and the possibility to use a VAX station. So I should like to know the characteristic and the cost of all three versions and if in the price are included the FORTRAN source files. Carlo ADAMO Carlo Adamo Dipartimento di Chimica via Mezzocannone 4 I-80134 Napoli ITALY Tel +39-81-5476504 fax +39-81-5527771 e-mail: ADAMO@CHEMNA.DICHI.UNINA.IT ----------------------------------------------------------------------------------- From: IN%"AHOLDER@VAX1.UMKC.EDU" "Andy Holder" 14-SEP-1992 21:25:10.92 To: IN%"ADAMO@chemna.dichi.unina.it" CC: Subj: AMPAC 4.0 Dr. Adamo, Thank you for your interest in AMPAC. To answer your questions, I am assuming that you are at an academic institution. If this in NOT the case, please let me know and I will requote prices to you. I have sent some additional material to you in the mail describing the features of AMPAC 4.0 and if you have any specific questions, please feel free to contact us. We have both IBM RS6000 and VAX versions of the programs available. Our graphics inter- face is is standard X11/Motif and runs on both of these systems. We would suggest that rather than buying a copy of the GUI for the PC, that you invest in an X-Windows emulator and run the GUI on the RS6000 or the VAX and view it on the PC. I have enclosed an article from a trade magazine with several solutions to this problem. In terms of software, you need X windows to run our executable. The academic price for each copy of AMPAC and GUI is $800. The source code is NOT provided with this package. We are willing to release limited versions of source code to developers, but we must protect our product. I hope that you understand. Andrew Holder =-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-= DR. ANDREW HOLDER Assistant Professor of Computational/Organic Chemistry Department of Chemistry || BITNET Addr: AHOLDER@UMKCVAX1 University of Missouri - Kansas City || Internet Addr: aholder@vax1.umkc.edu Spencer Chemistry, Room 315 || Phone Number: (816) 235-2293 Kansas City, Missouri 64110 || FAX Number: (816) 235-1717 =-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-= -------------------------------------------------------------------------------- Dear prof. Holder, thank you for your answer to the inquiry of my coworker dr. Carlo Adamo. I completely agree, of course, on the defence of commercial rights, but, in the case of AMPAC4 this would include, at most the graphical kernel. In all theoretical chemistry laboratories there is the competence, the habit and, often, the necessity to develop or adapt to specific purposes quantum mechanical packages like MOPAC or GAUSSIAN.Very often this provide also scientific feedbak to the original developers of the program. I am, therefore, not interested just to run the AMPAC package and think that the diffusion of a protectionistic policy concerning quantum mechanical software would strongly reduce scientific cooperation between different groups. On these grounds we would like to know if there is any way to obtain the souce files at least of the computational part of AMPAC 4.0. With my best regards Vincenzo Barone (Professor of Theoretical Chemistry) P.S. my mail address, etc. are the same as those of dr.Carlo Adamo ------------------------------------------------------------------------------- From: IN%"AHOLDER@VAX1.UMKC.EDU" "Andy Holder" 18-SEP-1992 17:04:56.85 To: IN%"ADAMO@chemna.dichi.unina.it" CC: Subj: AMPAC 4.0 Dear Professor Barone, I appreciate your reply to my earlier message. I agree to some extent with your ideas on the accessibility of quantum chemistry codes. We do allow developer's to have source code for specific purposes in dev- elopment, but this is on a case by case basis, and only under very carefully controlled circumstances. You already realize that the source code is our PRODUCT and if lost and copied, is probably the end of our company and the end of the rapid and organized progress of semiempirical methods. There are others in the world who have and would take unfair advantage of this situation. "Homegrown" modifications, while they may in the end advance science, often lead to wasted time and effort. We are attempting to halt the proliferation of this code and keep one "official" version. We are very happy and indeed anxious to have items contributed. There are already a number of collaborators working with us we hope to add more. We have a firm policy on how this will be handled and full credit will be awarded. We feel that these policies will lead to an overall improvement of the utility of our methods. I you have a specific contribution that you would like to make, please contact us and we will be happy to talk with you about this. Thank you, Andy Holder =-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-= DR. ANDREW HOLDER Assistant Professor of Computational/Organic Chemistry Department of Chemistry || BITNET Addr: AHOLDER@UMKCVAX1 University of Missouri - Kansas City || Internet Addr: aholder@vax1.umkc.edu Spencer Chemistry, Room 315 || Phone Number: (816) 235-2293 Kansas City, Missouri 64110 || FAX Number: (816) 235-1717 =-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-= From feng@sgi.chem.temple.edu Mon Jun 28 11:32:03 1993 Date: Mon, 28 Jun 93 15:32:03 -0400 From: feng@sgi.chem.temple.edu (Feng Chen) Message-Id: <9306281932.AA07666@sgi.chem.temple.edu> To: chemistry@ccl.net Subject: help: tar file on PC Hi: Is there any public domain DOS software availabel that can untar (tar -xvf) the file which is generate on the UNIX machine on PC. DOS or MS-Windows version are all welcome. Thank you very much for yor help. -- TTTTTTTTTT Feng Chen -- feng@sgi.chem.temple.edu II Tel: (215)204-5899 FAX: (215)204-1532 II II Dept of Chem, Temple Univeristy, Phila, PA 19122 TTTT ---------------------------------------------------------------------- From "PSI%SURFNET.1412007::MOIRA::groot"@caos.caos.kun.nl Mon Jun 28 04:00:53 1993 Date: Mon, 28 Jun 1993 09:56:28 METDST From: "PSI%SURFNET.1412007::MOIRA::groot"@caos.caos.kun.nl Subject: interaction function To: CHEMISTRY@ccl.net Message-Id: <01GZWOPWQ9KYAAU05U@caos.caos.kun.nl> Dear Netters, Last week I posted the following question to the Comp-Chem-List: >I have a series of noncovalently bound enzyme-inhibitor complexes for which >the 3D-structures have been determined/modelled. >I am trying to find computational methods that will allow me to estimate >the binding between the enzyme and these inhibitors. In other words: does >somebody know of A VALIDATED (published) INTERACTION FUNCTION ? Are >there papers in which experimentally determined binding data are correlated >with calculated interaction energies? >Since I am interested in both a large number and a wide variety of inhibitor >structures I don't think free energy perturbation methods will help me with >respect to this. About 10 persons responded to my question (many thanks!) or expressed their interest in the answers I would get. From the various responses I got I would say that: * the problem is very much alive both in industry and at academia * a number of people are collecting the combination of experimental structures and binding data in order to test methodology * systems under study vary from enzyme-inhibitor to antigen-antibody complexes * some scientists report successes with "simple" methods (neglect of solvation, conformation, entropy, etc) while others prefer working with more sophisticated methodologies. * nobody claimed to have found the ultimate answer or as Bruce Bush (one of the respondents) said "So the problem is by no means solved even at the crudest level." If this mailing results in more reactions, I will again try to summarise them and mail them to the Comp-Chem-List. Peter Grootenhuis (grootenhuis@akzo.akzo.400net.nl) ======================== SUMMARY OF THE RESPONSES ======================== Kate Holloway (kate.holloway@merck.com): ======================================= I am in the process of writing up some work on HIV protease inhibitors which is directly applicable to the question you ask. I too had too many inhibitors to use a technique as time-consuming as FEP, so I tried other more simpler methods and found that, at least for HIV protease inhibitors, there was a very good correlation (R2 of about 0.8) between the molecular mechanics intermolecular energy component and the measured IC50 (and this was with the enzyme held fixed, only the inhibitor moving!). However, this was only true with our in-house force field MM2X (developed by Tom Halgren), not with CHARMm (R2 of about 0.5). I have not tried AMBER. Using the correlation equation we derived for a set of between 30 and 60 inhibitors we were able to make fairly accurate predictions of inhibitor activity prior to synthesis. Unfortunately, when we tried to improve the accuracy of our calculations by including enzyme flexibility, solvation, etc., we were not successful, but that work is not completed. Arne Elofsson (arne@mango.mef.ki.se): ==================================== There was a paper by M. Levitt in science last year/. Where he correlated between binding strength and energy. This paper has been challenged by van Gunsteren & Marks IN (JMB) i think this year ==> W.F. van Gunsteren and A.E.Mark, J. Mol. Biol. 227 (1192) 389-395. ==> C.Lee and M.Levitt, Nature 352 (1991) 448-451 ==> (added by PG) Jerome Gabriel (gabriel@jg1.bchem.temple.edu): ============================================= ...I start off by minimising the energy of an inhibitor-gp120 complex. Then I calculate the potential energy of the inhibitor alone and of gp120 alone. From this data I can calculate what I call the interaction potential: E(cmplx) - { E(gp120 alone) + E(inhibitor) } . We have plotted the interaction energy versus apparent Kd for several known inhibitor and get a very nice linear relationship... Tom Hendrickson (hendrick@humbert.agouron.com): ============================================== ... Here at Agouron, we have many crystal structures of enzyme-inhibitor complexes. The study that we did involved the enzyme thymidylate synthase and about 31 inhibitors complexed to it. The method used was minimization of a substructure of the protein with the program MacroModel, developed at Columbia University. There is an implicit solvation potential in the force field which has been shown to work quite well with small organic molecules. This work was presented by me at the Molecular Graphics meeting in Interlaken, Switzerland this past month. I will probably write the work up shortly for publication. The overall method is quite simple, but a bit lengthly to explain. The resultant "binding energy" is not the absolute binding free energy, but the difference can be rationalized in terms of misssing consderations of loss of configurational entropy associated with translation and rotation and conformational entropy of the side chains of the protein and torsional rotations of the free ligand. We have shown that on can get results equivalent to free energy perturbation calculations if the changes primarily involve the enthalpy in the free energy. In general, the method may be good for evaluating the output from 3D searches of databases or for evaluating small changes to a known inhibitor structure. Since it is essentialy a minimization technique, it runs fairly quickly... Richard Judson (rsjuds@california.sandia.gov): ============================================= ... There are no refs in what follows which include the works of Art Olson (at Scripps) but I am familiar with the work and will dig some more and send you the ref. Also there is something called HINT which purports to do something like docking into a FIELD of properties. Peter Goodford's GRID has long done stuff like that. Of course there is LUDI from BIOSYM now. That helps construct molecules in a cavity . We saw it and it looks like it has some potential but we are evaluating it at present. Finally there is the CAVEAT (from Paul Bartlett) program that lets you find molecules whose stored conformers (in the CSD) match some set of vectors so that you can use them as templates for building the 3D functionality constellation that you want... Author BL Stoddard, DE Koshland Title Molecular Recognition Analyzed by Docking Simulations - The Aspartate Receptor and Isocitrate Dehydrogenase from Escherichia-Coli Source Proceedings of the National Academy of Sciences of the United States of America 90: 4 (FEB 15 1993) Page(s) 1146-1153 Keywords Protein Docking; Drug Design; Energy Minimization; Substrate Binding; Receptor Signaling KeyWords+ PROTEIN-PROTEIN-INTERACTION; MALTOSE-BINDING; PHOSPHORYLATION; ENZYME; COMPLEMENTARITY; CHEMORECEPTOR; SPECIFICITY; CHEMOTAXIS; LIGAND; SITE Berkeley, CA 94720 Author SH Rotstein, MA Murcko Title GenStar - A Method for Denovo Drug Design Source Journal of Computer - Aided Molecular Design 7: 1 (FEB 1993) Page(s) 23-43 Keywords Drug Design; Protein Structure; Drug Ligand Interactions; HIV Protease Inhibitors; Carbonic Anhydrase Inhibitors; Ligand Design; Protein Active Site; Enzyme Inhibitors; FKBP-12 Inhibitors KeyWords+ HUMAN IMMUNODEFICIENCY VIRUS-1; PRIMARY STRUCTURE GENERATION; ASSISTED MOLECULAR DESIGN; HIV-PROTEINASE- INHIBITORS; HYDROGEN-BONDING REGIONS; FAVORABLE BINDING-SITES; CARBONIC ANHYDRASE-II; CAVITY SURFACE- AREA; HYDROPHOBIC INTERACTIONS; ABINITIO CALCULATIONS Author J Cherfils, S Duquerroy, J Janin Title Protein-Protein Recognition Analyzed by Docking Simulation Source Proteins - Structure Function and Genetics 11: 4 (1991) Page(s) 271-280 Keywords Antigen Antibody Recognition; Protease-Inhibitor Complexes; Simulated Annealing; Energy Refinement; Docking Algorithm KeyWords+ PANCREATIC TRYPSIN-INHIBITOR; ANTIBODY-ANTIGEN COMPLEX; ACCESSIBLE SURFACE-AREA; 3-DIMENSIONAL STRUCTURE; CRYSTAL-STRUCTURE; SHAPE COMPLEMENTARITY; ENZYME-INHIBITOR; BOVINE TRYPSIN; BINDING-ENERGY; LYSOZYME Author SH Northrup, HP Erickson Title Kinetics of Protein-Protein Association Explained by Brownian Dynamics Computer Simulation Source Proceedings of the National Academy of Sciences of the United States of America 89: 8 (APR 15 1992) Page(s) 3338-3342 Keywords Diffusion Controlled Reactions; Antibody Antigen Complexation; Self-Assembly; Lengthy Collisions KeyWords+ CYTOCHROME-C PEROXIDASE; ORIENTATION CONSTRAINTS; ROTATIONAL DIFFUSION; BINDING; DISSOCIATION; DOMAINS; ACTIN; RATES; MODEL Author L Banci, S Schroder, PA Kollman Title Molecular Dynamics Characterization of the Active Cavity of Carboxypeptidase-A and Some of Its Inhibitor Adducts Source Proteins - Structure Function and Genetics 13: 4 (AUG 1992) Page(s) 288-305 KeyWords Molecular Dynamics; Catalysis Carboxypeptidase; Ligand Binding KeyWords+ REFINED CRYSTAL-STRUCTURE; D-PHENYLALANINE; GROUND- STATES; NUCLEIC-ACIDS; FORCE-FIELD; COMPLEX; SIMULATION; BINDING; RESOLUTION; PROTEINS Here is the Olson Reference: Title: AUTOMATED @DOCKING@ OF SUBSTRATES TO PROTEINS BY SIMULATED ANNEALING Author(s): GOODSELL DS; @OLSON AJ@ Corporate Source: SCRIPPS CLIN & RES FDN,RES INST,DEPT MOLEC BIOL,10666 N TORREY PINES RD/LA JOLLA//CA/92037; SCRIPPS CLIN & RES FDN,RES INST,DEPT MOLEC BIOL,10666 N TORREY PINES RD/LA JOLLA//CA/92037 Journal: PROTEINS-STRUCTURE FUNCTION AND GENETICS, 1990, V8, N3, P 195-202 George Seibel (seibelgl@smithkline.com): ======================================= ... The most interesting thing that I know of right now is Hans Bohm's Ludi potential. In my notes from the York meeting, I have it as 6 kJ/mole for each hydrogen bond, and 100 J/mol*Angstrom**2 for everything that is not involved in a hydrogen bond. As far as I know it doesn't have any sort of penalty for hydrogen bonds *not* made... but I'm not sure about that. He had a paper in JCAMD within the last year or so, which I don't have here right now. He may or may not have discussed the potential there. We have a postdoc here named Jonathan Keske who is working on this very problem. He has gathered a huge database of complex structures from the PDB, and looked up binding constants for all of them. He's now working on developing an interaction potential based on this data... ...I think that the Ludi potential or something like it is probably the way to go here for now. Bohm didn't say anything about the functional form, i.e. the distance dependence. I would guess that "hydrogen bond" is probably any donor-acceptor distance of less than about 3.2 Angstroms or so, and they all get the same energy. He showed a graph of his potential against Ki for a number of complexes (like maybe 20 or 30 unidentified receptor/ligand systems) and it was pretty linear. Let me know if you hear about any good papers along these lines... Herman van Vlijmen (vlijmen@tammy.harvard.edu): ============================================== ... Two papers that are of interest are: J. Novotny et al. On the attribution of binding energy in antigen-antibody complexes McPC603, D1.3, and HyHel-5. Biochemistry, 28:4735-4749, 1989. G. Klebe and U. Abraham. On the prediction of binding properties of drug molecules by comparative molecular field analysis. In addition, I can tell you that Amedeo Caflisch, with us at the Karplus lab, has improved the Novotny-type calculation considerably, by using Poisson-Boltzmann electrostatics, and a more accurate estimation of the conformational entropy loss. Bruce Bush (Bruce_Bush@merck.com): ================================== Bruce L. Bush, Molecular Systems / Biophysical Chemistry, Merck Research Labs, Rahway NJ 07065 USA (908) 594-6758 In general, binding (L+R -> LR) in solution can be regarded as proceeding in three steps: removing species L and R from water (i.e. desolvating each species); letting them interact in vacuum (L + R -> LR, whose energy is given by standard empirical energy functions such as Lennard-Jones + Coulomb); and then resolvating LR, thus partly reversing the desolvation of L and R separately. As this scheme indicates, one way to get at binding energy in solution is to find the solvation (desolvation) free energy of each species separately. Barry Honig and his group (Kim Sharp, Michael Gilson, Anthony Nicholls) have published many papers in Biochemistry, Proteins, etc. on estimating these energies. Their approach is to divide the solvation free energy into a charge-dependent or "dielectric" solvation energy, and a non-charge-dependent, cavity-formation, or "hydrophobic" energy. Adding all of these to the in vacuo energy gives, in principle, the full binding energy in solvent. The DelPhi program (Biosym Technologies, inc.); produced by Honig et al calculates the dielectric part alone. The POLARIS program (Molecular Simulations, Inc.) of Arieh Warshel and his group makes a similar decomposition of the energy but represents the "water" as a grid of dipoles rather than as a continuum. Another approach is to create an effective potential, usually a pairwise potential, which somehow incorporates effects of solvent. Scheraga's ECEPP program takes this approach. Note however that ** An interaction function which claims to reproduce binding energy in an aqueous medium is *necessarily* non-additive. ** Thus the function cannot simply be a sum over atom pairs (i,j) of some f(distance(i,j)). At the very least, the interaction function may involve calculating some property p(i) of each atom (such as its surface exposure) which is not additive over atom pairs, and using this p(i) to modulate a pairwise interaction (for example, p(i)*f(distance(i,j))). The BATCHMIN or MACROMODEL energy function, described in publications by Clark Still's group, is a pairwise effective potential which is non- additive in this sense. Still claims that this function produces good results for free energy of aqeuous solvation of organic molecules and ions -- a necessary but not sufficient condition for giving binding energies. You want to compare widely different ligands or binding geometries. This is an extremely difficult problem which calls for very SIMPLE and rough estimates. One study which did produce a regression (rather than a first-principles calculation) of measured binding affinities, involving 9 crystallographic structures of thermolysin-inhibitor complexes, is: TI: Definition and display of steric, hydrophobic, and hydrogen-bonding properties of ligand binding sites in proteins using Lee and Richards accessible surface: validation of a high-resolution graphical tool for drug design. AU: Bohacek-RS; McMartin-C AD: Pharmaceuticals Division, CIBA-GEIGY Corporation, Summit, New Jersey 07901. SO: J-Med-Chem. 1992 May 15; 35(10): 1671-84 Of course, a regression is not a prediction, and it is not clear whether the "explanatory" factors (numbers of polar / nonpolar atoms involved in the interface, etc.) are really explanatory for other systems. In fact, the reported r-square of 0.99 becomes far worse (? 0.4 ?) if one additional thermolysin inhibitor is included in the fit. So the problem is by no means solved even at the crudest level. -------------------------------------------------------------------------------- E-mail address: grootenhuis@akzo.akzo.400net.nl ==> The "reply" or "answer" commands will NOT work for answering this mail. You need to specify the whole e-mail address. Postal address: Organon International bv --- Dr. Peter D.J. Grootenhuis --- CMC group KR1004 P.O. Box 20 --- 5340 BH OSS --- The Netherlands Phone: 31-4120-61920 --- Fax: 31-4120-62539 -------------------------------------------------------------------------------- From tqi@sunrnp.UFBA.BR Mon Jun 28 13:18:18 1993 Date: Mon, 28 Jun 93 18:18:18 EST From: tqi@sunrnp.UFBA.BR (Tecnologia Quimica e Informacao) Message-Id: <9306282118.AA05961@sunrnp.UFBA.BR> To: chemistry@ccl.net Subject: modsim Hello, I would like to have a help to identify ftp SERVERS in the area of modeling and simulation of chemical processes. Thanks Adalberto Cantalino E-MAIL: tqi@sunrnp.ufba.br  From eve@amethyst.sri.com Mon Jun 28 16:47:05 1993 Date: Mon, 28 Jun 93 13:46:53 -0700 From: eve@amethyst.sri.com (eve gail zoebisch) Message-Id: <9306282046.AA16139@amethyst.sri.com> In response to the comments and queries of Mark A. Thompson: >A couple of years ago, I coded the MNDO, AM1, and PM3 methods, >in Argus, completely from scratch. This included all the relevant >integrals, using the local symmetry-based method as the papers >suggested, etc. I'm am glad to see the MNDO style methods could be independently built from information in the literature. This is a true test that the method is reproducible, although it appears additional testing of the individual terms is needed. My apologies for the typos in the AM1 paper and you have my great appreciation for your efforts in working through the ambiguities of the published material. >I recall one specific instance that left me a little breathless: >I was trying to work out the units used in the published values >of the parameters used in nuc-nuc repulsions (especially the >K,L,M params used in the gaussian terms). It turns out that, >to get consistent answers, one had to take the K,L,M >parameters directly from the literature at face value, >use distances in angstroms, nuclear charges in atomic units, >and one ended up with energy in eV. It's as if all the relevant >conversion factors are somehow buried in these parameters. After >some gynmastics, I did manage to coax everything into atomic units, >which is what Argus uses internally. Jimmy Stewart and Walter Thiel are better suited than I to comment on the specifics of the code for semi-empirical methods. However, regarding your query about the units used in AM1. Semi-empirical methods use terms derived from experimental values from the literature, where the units used by the experimentalist were maintained where possible. For example the values used for the one center integrals, upon which the other integrals are based, were reported in electron volts >from spectroscopy data (Oleari et al). Maintaining the units used by experimentalist makes it easier to compare terms with experiment during method development. The gaussian correction for the nuc-nuc term was a purely empirical correction. Molecular properties which are strongly influenced by the gaussians are geometries and heats of formation. Since experimental values for geometries are generally reported in Angstroms or nanometers, Angstrom units were used. Since the nuc-nuc energy term (which includes the repulsion between the core electrons) was added to the electronic energy calculated from the density matrix (calculated in electron volts), electron volts were the natural unit to use for energy. In general molecular properties and the values for individual terms were output in the units found in the experimental, not the theoretical, literature. Dipole moments were reported in Debye, heats of formation in kcal/mole, and ionization potentials in electron volts. The intent in semi-empirical methods was to utilize Hartree Fock methodology where the terms for the matrix elements were deduced from experimental results. Thinking in the units used by experimentalist aided the effort. E. G. Zoebisch zoebisch@crvax.sri.com From carlos@molout.tutkie.tut.ac.jp Mon Jun 28 22:24:42 1993 Date: Tue, 29 Jun 93 10:56:11 jst From: carlos@molout.tutkie.tut.ac.jp (CC) Message-Id: <9306290156.AA21002@molout.tutkie.tut.ac.jp> To: CHEMISTRY@ccl.net Subject: TORSIONAL ANGLES Please I need your help. I'm doing some conformational analysis and I need information o the torsional angles of 3,4,5,6 and 7 memebered rings. Could anybody of you dear netters supply this information. I thank you in advance: Carlos A. Del Carpio