From chemistry-request@ccl.net Fri Oct 4 05:46:46 1991 Date: Fri, 4 OCT 91 10:37:46 +0100 From: EA_MOORE%VAX.ACS.OPEN.AC.UK@OHSTVMA.ACS.OHIO-STATE.EDU To: chemistry@ccl.net Subject: Protein-macromolecule interaction/molecular mechanics Status: R Dr.W.G.Richards at Oxford university, U.K. is an expert on drug/receptor interaction and may be able to help you. He has written a book Quantum Pharmocology Butterworths,London (2nd Edn. 1983). I don't know of any FTP able molecular mechanics but the Oxford Molecular package can be obtained through a site licence not exceeding 600 pounds sterling per annum. Apply to CHEST@BATH CHEST Bath University Computing Service Claverton Down BATH BA2 7AY England. From chemistry-request@ccl.net Fri Oct 4 10:54:46 1991 Date: Fri, 4 Oct 91 09:59:45 EDT From: balbes@osiris.rti.org (Lisa M. Balbes) To: chemistry@ccl.net Subject: Summary: Protein-small molecule interactions Status: R WOW ! I guess I hit a good topic. I got quite a few responses, and several people suggested that the a discussion on the BB would be more appropriate. So, I am posting a brief summary of the responses I have had so far. Most of the solutions are computationally intensive routines, which is what I was afraid of. If anyone else has a simple, elegant solution, there is a large community out there waiting for it. Summary follows. All typos mine, all responses paraphrased. I will send the full text of replies to anyone who requests it. It's 520 lines - so far. Many Thanks to everyone who answered - Does anyone else have something to add? Lisa NOTE: I posted both the original question and summary to both the comp chem mailing list (chemistry@ccl.net and the sybyl mailing list (sybyl@quant.chem.rpi.edu). Replies should probably be sent to both as well. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ***** From: Carlos Faerman Program DOCK, by I. D. Kuntz. This tries to fit rigid bodies against the receptor and then scores them according to a function that tells you how good this fit of spheres is. Once that step is done you could use CHEMPROP wich turns on the electrostaiatic potential and possibly hydrogen bonds and analyze these complexes. Although it may sound rudimentary it gives a good idea of the orientations you should discard. References: J. Med. Chem. (1988) 31,722-729. (algorithm) Proc. Natl. Acad. Sci. USA (1990) 87,6644-6648. (application to HIV protease) ***** jpj@lotus.medicine.rochester.edu (Jeffrey P. Jones) Use free energy difference calculations using either a slow growth or a perturbation program. This type of calculation is accurate to between 1 and 0.2 kcals. This method eliminates much of the problem associated with poor sampling. See Singh et. al. JACS 1987, 109, 1607(AMBER), Beveridge, Annu. Rev. Biophys. Biophys. Chem. 1989, 18, 431 (Great review although it is now dated) , Mitchell J. Comp. Chem. 1991, 12, 271. This is a lot of work but it really is great! ***** From: Yvonne Martin MARTIN@cmda.abbott.com Jeff Howe at Upjohn does what you are interested in by a standard potential energy calculation and then adding in the solvation-desolvation term (essential) by using Scheraga's terms. Jeff has a manuscript in press in which the computer designs molecules to fit a binding site. For this to be reliable, he has to be able to compare and rank the various suggestions. The above method seems to work well. For example, they successfully build a number of ligands for which they know experimentally how they bind. The program also suggests the analogue found experimentally. ***** From: "Leonore A. Findsen" The big question here is what exactly are you looking for. The method of QSAR combines a number of different factors to generate a number or a volume and then you look at a range of numbers. However, you determine the factors that QSAR will analyze. I use molecular dynamics to look at protein-drug interactions, but I am looking at specific non-covalent bonds. Another methodology is to use the relative free energy of binding of two similar drugs. Or you can do a conformational analysis if the drug and see how the collective volume fits. I don't believe that there is just one methodology for looking at protein-drug interactions (or at least I hope there isn't or the field I am in might colapse). ***** From: martin@link.sunet.se (Martin Norin) We have just (today actually) submitted a paper on how to calculate the enantioselectivity of enzymes, e.g. the free energy difference between the transition state of the reaction of enantiomers of a small substrates (esters) catalyzed by an enzyme (chymotrypsin). We have compared the difference in potential energy between the transition state of each enantiomer (bound to the enzyme) with experimental data. The results agrees with experimental data semiquantitatively.We have used molecular mechanics and dynamics in this work. We also have used specific methods to calculate point charges of substrate atoms. Also has had good luck with GRID. This program looks for interesting interaction areas between molecules, especially between a small molecule and a protein. In short the program rolls a probe, which may be a part of a drug, over the target molecule and measures the interaction energy between the probe and the target at every grid point. It a unique force field which probaly is the best in the area right now (my personal opinion). Original Reference: J. Med. Chem (1985) _28_, 849-857. Also Reynolds, C. A., Wade, R. C., Goodford, P. J. "Indentifiying targets for bioredictive agents: using GRID to predict selective bimding regions of proteins." J. Mol. Graphics. 7: 103-108, 1989. GRID is a computational procedure for detecting energetically favourable binding sites on molecules of known structure. GRID can distinguish between selective binding sites for different Probes. The Target and Probe can be studied in a condensed phase such as water, so that results from GRID are particularly relevant to biological systems in which the "in vacuuo" approximation can be misleading." ***** From: bio320@cvx12.inet.dkfz-heidelberg.de (Friedrich Rippmann) A recent state-of-the-art paper on interaction energies of ligands to proteins is e.g. DM Ferguson, RJ Radmer, PA Kollman Determination of Relative Free Binding Energies of Peptide Inhibitors yo the HIV-Protease J. Med. Chem. 34, 1991, p. 2654-2659 I think it is clear that you have to apply some kind of a molecular dynamics protocol to get something like an interaction energy. Probably it is not realy necessary to calculate deltaG (or rather deltadeltaG) as in the approach detailed in the above paper (there are many such approaches now using perturbation theory/thermodynamic cycle to get delta G). All these approaches are rather computationally expensive, and there are usually many problems (charges seem to be very important sometimes) before you get reasonable results. To overcome the comp. time problems I devoloped a relatively simple MD protocol. Basically I cycle through 1) minimization 2) clculation of (non-bonded) interaction energy 3) dynamics and again 1) and so on. I then average the energies in 2) and get an interaction value with a standard deviation (I usually perform ca. 20 cycles). A plot of these energies (for a number of compounds) against experimentally determined delta Gs is nicely linear, so from a progmatic point of view it works (should read pragmatic, of course). I have finished a paper on that, but not submitted it yet. Certainly many people would be interested in an easy way to get these energies, but nobody has got a simple solution yet. ***** From: EA_MOORE%VAX.ACS.OPEN.AC.UK@OHSTVMA.ACS.OHIO-STATE.EDU Dr.W.G.Richards at Oxford university, U.K. is an expert on drug/receptor interaction and may be able to help you. He has written a book Quantum Pharmocology Butterworths,London (2nd Edn. 1983). I don't know of any FTP able molecular mechanics but the Oxford Molecular package can be obtained through a site licence not exceeding 600 pounds sterling per annum. Apply to CHEST@BATH CHEST Bath University Computing Service Claverton Down BATH BA2 7AY England. ***** From: Rick Loncharich There is a paper by Pettitt and Karplus Top Mol. Pharmacol. V3, 1986, 75-113 entitled "interaction energies: their role in drug design". Application of the technique is in Lau and Pettitt J. Med. Chem 1989, 32, 2542-2547. Be careful there are minor points to this procedure that are not explicitly written down. %%%%%%%%%%%%%%%%%%%%% balbes@osiris.rti.org %%%% standard disclaimer %%%%%%%%%% Lisa M. Balbes, Ph.D. Research Triangle Institute Life would be boring without problems. P. O. Box 12194 919-541-6563 Research Triangle Park, NC 27709-2194 919-541-6767 xt 6563 (Msgs 24 hr) From chemistry-request@ccl.net Fri Oct 4 13:08:09 1991 Date: 04 Oct 91 17:26:15 EDT From: Subject: Periodic SCF for polymers To: chemistry@ccl.net Status: R E. M. EVLETH Dynamique des Interactions Moleculaires Universite Pierre et Marie Curie 4 Place Jussieu, Tour 22, Paris 75005 (1) 44 27 42 08 UDIM018 at FRORS31 We are looking for a periodic Hartree-Fock ab-initio type program handling polypeptides. We use Crystal here but are sending out this general inquiry to see if any other similar beasts are around. Thanks for any information or even rumours. The above address is EARN-BITET. E. M. EVLETH