From dons@hamilton.math.missouri.edu Tue Aug 4 15:01:30 1998 Received: from math.missouri.edu (math.missouri.edu [128.206.72.13]) by www.ccl.net (8.8.3/8.8.6/OSC/CCL 1.0) with SMTP id PAA06090 Tue, 4 Aug 1998 15:01:29 -0400 (EDT) Received: from hamilton.math.missouri.edu by math.missouri.edu via ESMTP (940816.SGI.8.6.9/940406.SGI) for <@math.missouri.edu:chemistry@www.ccl.net> id OAA05238; Tue, 4 Aug 1998 14:01:31 -0500 Received: by hamilton.math.missouri.edu (940816.SGI.8.6.9/940406.SGI) for chemistry@www.ccl.net id NAA27849; Tue, 4 Aug 1998 13:28:37 -0500 From: "Don Steiger" Message-Id: <9808041328.ZM27847@hamilton.math.missouri.edu> Date: Tue, 4 Aug 1998 13:28:35 -0500 X-Mailer: Z-Mail (3.2.0 26oct94 MediaMail) To: chemistry@www.ccl.net Subject: Drug design - summary. Mime-Version: 1.0 Content-Type: text/plain; charset=us-ascii Status: RO Content-Length: 11442 Below is a summary of the replies to a question I recently posted. I would like to thank everybody who replied to the question. First the question. > I am a math graduate student and working with one of the theoretical chemist at > the university here I developed a multipole algorithm for calculating coulomb > interactions. With some modifications, this method can be used as a rapid > screening procedure for the electrostatic version of the docking problem. > The chemist that I am working with feels that this is a very important problem > in the area of drug design and that I should pursue it further. In helping me > to decide if I should pursue this, I was wondering if someone could briefly > summarize the state of the art in this field. The reply summary follows. > Hierarchical multpole methods are very usefull mathematical > tools in chemsitry. See my page for papers with bibliography > on this topic. > > On the other hand, attempting to fit or parameterize chemical > interactions with multipoles (or other functions) is an art, not a > science, as there are an infinite number of posibilities. My two > cents is to focous on mathematical tools, and to avoid at all > costs anything that looks like a parameterization. > > Cheers, Matt > > +-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+-+ > Matt Challacombe > Los Alamos National Laboratory http://www.t12.lanl.gov/~mchalla/ > Theoretical Division email: mchalla@t12.lanl.gov > Group T-12, Mail Stop B268 phone: (505) 665-5905 > Los Alamos, New Mexico 87545 fax: (505) 665-3909 ______________________________________________________________________________ I am somewhat familiar with the work of the above individual. Two very interesting and novel papers of his are the following. 1) Fast assembly of the Coulomb matrix: A quantum chemical tree code. J. Chem. Phys. 104(12) pages 4685-4698. 2) Linear scaling computation of the Fock matrix. J. Chem. Phys. 106(13) pages 5526-5536. Don _____________________________________________________________________________________________________________________________ > The difficulty here, as I understand it, is that multipole methods > are useful only in the "far field" case, while it is nearby interactions > that predominate in protein/ligand interactions. I looked into > multipole methods for a slightly different, but related, purpose > some years back and decided that it wasn't worth it. But don't let > my decision for a somewhat different problem and a less-than-perfect > understanding of multipole expansions discourage you from looking into > the problem more deeply yourself. Just make sure that the part of the total > calculation that you want to speed up is a sufficiently large part of > the total calculation that it makes a difference. Remember that a > 90% speed-up of 10% of the calculation is only a 9% improvement overall. > > > regards, > > Ethan A Merritt > > ----------------------------------------------------------------- > Dept of Biological Structure K428b Health Sciences > University of Washington SM-20 (206)543-1421 > Seattle, WA 98195-7742 merritt@u.washington.edu Comment. Multipole expansions have decent convergence only in the far field case. However, I think this problem can be ameliorated with a couple of tricks. The first is to fragment the molecules and compute the multipole moments for each of the fragments. The second trick would be to use non-linear convergence acceleration methods on the multipole expansion. This idea has been tried on a spherical harmonic multipole expansion by H.H.H. Homeier in a paper recently published in the Internet Journal of Chemistry; http://www.ijc.com/articles/1998v1/28. What I suspect to be the most difficult problem to work around are the induced effects. Don ________________________________________________________________________________ > Greengard-Rokhlin algorithm. Leslie Greengard is at Yale. > I don't know who has implemented this for finding molecular > energies. Use Science Citation Index to find out. Can > you treat molecular models in solution, with one > dielectric constant inside the molecule, and a second, > in general different, dielectric constant outside the > molecule? I have a fast diffusion method for solving these problems. > We are using it to calculate solvation energies of macromolecules. > > > Best, > > Jim Given > > Center for Advanced Research in Biotechnology _______________________________________________________________________________ > While purely electrostatic interaction potentials were developed and > tried a few decades ago, they remain a very important part of > computational chemistry. At present, most people do not use multipolar > representations for electrostatic interations (they stick with monomers > alone or use bond dipoles) since the computational time for multipolar > interaction calculations is significantly greater. Don Williams > (Kentucky, I think) has some code which will fit electrostatic > potentials to a set of multipoles, of both atom and bond centered > character. I believe that this code can also be used to compute and > export potentials using the derived multipoles. There are a number of > other groups who have worked in this area, so please do not assume that > this posting is comprehensive. Price, Stone and our own group > (Breneman) have also worked in this area. Earlier workers are Ritchie > and Hirschfeld. There is a rich literature in this area, but there is > always room for good ideas. > > Prof Curt Breneman > RPI Chemistry Department ________________________________________________________________________________ > That work sounds very interesting and I would like to hear about any useful > replies you get please. My colleague, Frank Burden (Chemistry Department > Monash University) have been working on molecular multipoles for screening > applications for some time. We are basically improving the methods > developed by Silverman and Platt (Platt, D.E.; Silverman, B.D. J. > Computat. Chem. (1996), 17, 358-66; > Silverman, B.D; Platt, D.R. J. Med. Chem. (1996) 39, 2129-40). The > critical question for drug design is how you define your axis system for > the electric multipoles with respect to the inertial axes. If this can be > done correctly, the so-called 'alignment problem' (the need to superimpose > molecules which at act at the same receptor in a consistent way) can be > eliminated. We do not agree with how S&P have defined theirs by feel they > were on the right track. We have also added steric/inertial multipoles and > , in collaboration with Glen Kellogg at Virginia Commonwealth University, > have included 'hydropoles' (essentially expansions of the lipophilic > properties of drug molecules). > > We would be interested in hearing more about your work. Can you send us > any papers, reports, theses etc on what you have achieved? > > Cheers, > > Dave > > Dr. David A. Winkler Email: dave.winkler@molsci.csiro.au > Senior Principal Research Scientist Voice: 61-3-9545-2477 > CSIRO Molecular Science Fax: 61-3-9545-2446 > Private Bag 10,Clayton South MDC 3169 http://www.csiro.au > Australia http://www.molsci.csiro.au > > _______________________________________________________________________________ > Check out papers by > Greengard and Rokhlin, > S.Lustig and N.J.Wagner et.al. > sorry don't have them handy, > these are all quite recent publications, last maybe 4-5 years, > I am sure you'll find it in the database, > > Hope this helps, > Mike > > ------------------------------------------------------------------------------- > Michael J. Kotelyanskii Phone (814) 863 43 81 > Polymer Science Program FAX (814) 865 29 17 > Department of Materials Science and > Engineering kotelyan@plmsc.psu.edu > Pennsylvania State University http://www.plmsc.psu.edu/~kotelyan > University Park, PA 16802, USA ________________________________________________________________________________ > Yes, treating correctly Coulomb interactions in molecular simulations > (without using a cutoff in the list of interacting centers) is indeed an > important topic. The contest seems to have been won by smooth particle > mesh Ewald sums (SPME), which scales as O(N) like the fast multipole > technique, but with a much smaller costant factor, as I am said: see > T.A. Darden, D.M. York, L.G. Pedersen, J. Chem. Phys., 98, 10089 (1993); > U. Essmann, L. Perera, M. Berkowitz, T. Darden, H. Lee, L.G. Pedersen, > J. Chem. Phys., 103, 8577 (1995); P. Procacci and M. Marchi, J. Chem. > Phys., 104, 3003-3012 (1996); P. Procacci, T. Darden, M. Marchi, > J. Phys. Chem., 100, 10464-10468 (1996). > > Two references for the fast multipole method, which I admit to have > never read though, are K.E. Schmidt, M.A. Lee, J.Stat.Phys. 1223-1235 > (1991) and J. Shimada, H. Kaneko, T. Takada, J. Comp. Chem. 15, 28 > (1994). See also the book D.Frenkel, B.Smit, Understanding Molecular > Simulation, Academic Press (1996). > > It's not clear to me, however, if high accuracy and periodic boundary > conditions are needed in docking problems as well as in molecular > dynamics simulations. If they aren't, maybe the fast multipole method > which was originally devised for a cluster of ions is indeed a better > choice than SPME. > > Regards > > Dr. Guido Germano > > Research Assistant in Theoretical Physics, University of Bristol, England > Tel. +44-117-928 8755, http://www.phy.bris.ac.uk/staff/germano_g.html > ________________________________________________________________________________ > There is an abundance of reviews on drug design. Look at the book series, > Reviews in Computational Chemistry, edited by Lipkowitz and myself. > Particularly Vol. 5 (1994) and Vol. 11 (1997). These books will probably be > in your chemistry department library. Also, take a look at the May 1998 issue > of CHEMTECH magazine, p.19. Again it should be in your chemistry department > library. > > Don > Donald B. Boyd, Ph.D. > Editor, Journal of Molecular Graphics and Modelling > Department of Chemistry > Indiana University-Purdue University at Indianapolis > 402 North Blackford Street > Indianapolis, Indiana 46202-3274, U.S.A. > E-mail boyd@chem.iupui.edu ________________________________________________________________________________ > I suggest that you look at papers by S L Price (University College > London) to see applications of multipole calculations in molecular > modelling. However her work may not be directly applicable to > docking calculations: I think she is mainly interested in small- > molecule crystallographic modelling issues. Certainly multipole > calculations are an important technique in that area (although > they are rarely used in practice because the major modelling > software packages cannot handle them at present). I don't know > anything about docking myself so I cannot comment on how useful > they would be in docking calculations. > > -- > John Osborn > University of Bradford, UK. > Email j.c.osborn@bradford.ac.uk -- Don Steiger dons@hamilton.math.missouri.edu