Drug design - summary.
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-: at :-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-: at :-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-: at
:-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-: at :-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-: at :-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-: at :-bradford.ac.uk
--
Don Steiger
dons-: at :-hamilton.math.missouri.edu