Subject: summary: electrostatics using MD vs FDPB

From: "S. Roy Kimura" <[email-masked]>
Date: Mon, 23 Mar 1998 12:07:55 -0500 (EST)

Dear CCLers,

Here is a summary of responses to the question I posted a few weeks
ago concerning electrostatic calculations using MD versus continuum
methods.

I appreciate all of your responses and comments. Thank you very much.

Roy

-----
S. Roy Kimura
Molecular Engineering Research Laboratory
Department of Biomedical Engineering           email: [email-masked]
Boston Univesrity                              phone: (617)353-4726

---------------------- original question -----------------------------

I have a question regarding electrostatic calculations in proteins
relating to issues such as solvation, salt-bridge stability, or
binding energies. I have read that different workers have had varying
success in calculating electrostatic energies using the
Finite-Difference Poisson-Boltzman method. However, this method
suffers from the ambiguity of the dielectric constant of the protein
interior which, strictly speaking, shouldn't be considered a
homogeneous dielectric continuum in the first place.

I was wondering if anyone has made any progress in electrostatic
calculations by the full inclusion of solute motion, for instance by
conducting molecular dynamics or all-atom Monte Carlo simulations. I
realize that such a method will still neglect electronic polarization
but will at least correctly treat the inhomogeneity of the protein
interior, if it is possible to run long enough to adequately sample
the full electrostatic response. Moreover, I was thinking that
electronic polarization may still have a chance to be described by a
dielectric constant (eps = 2 to 4) superimposed on top of the explicit
solute motion which takes care of reorientational polarization.

I would appreciate if anyone could point me to some papers that
considers electrostatic calculations by averaging the response in MD
or MC simulations. I am interested specifically in the feasibility of
such calculations which must include solvent in some form (either
explicitly or implicitly).

I have read some of the works by Warshel, Aqvist, and King who seem to
have ideas along this line; however, they chose to describe the solute
and solvent through a set of variable dipoles on a grid. I am
interested in knowing if it is possible to capture reorientational
polarization through explicit consideration of solute atom motion.

-------------------------- reply 1 -------------------------------

These two papers might be of help:

M. K. Gilson and B. Honig, Biopolymers 25, 2097-2119 (1986)

T. Simonson, D. Perahia and A. T. Brunger, Biophys. J. 59, 670-690 (1991)

Good luck!

Gary

-------------------------- reply 2 -------------------------------

The work of Warshel an coworkers offers more than the semimicroscopic
PDLD method that treats the solvent as polarizable Langevin dipoles.
His program package ENZYMIX includes an all-atom MD program that treats
the solvent molecules explicitly (rigid 3-point water model,
similar to TIP3P). One difference to other MD programs is
that you can chose to include induced dipoles and/or induced forces
in the calculations (see F. Lee et al. J.Comp.Chem. (1993)).

Depending on what you are interested in you can use Free Energy Perturbation
or Linear Response Approximation methods to calculate binding affinites,
pKa-valaues, redox potentials or solvation energies. Especially the
linear response approximation is conceptually and practically capable of
quantifying reorientational (reorganizational) effects.
Nevertheless, the PDLD method is also able to deal with these effects,
introducing a scalaing constant epsilon that must not be confused with a
true dielectric constant but is merely a scaling factor that stands for
the contributions to the free energy that are not explicitly taken into account
(e.g., induced dipoles, the effect of change in water penetration upon
complex formation). As it turnes out, the PDLD results are much more stable
than the microscopic ones and for practical purposes this is often the
method of choice. Note also the recently published incorporation of the
Langevin dipole solvation model as an alternative to TOMASI in Gaussian.
A new program package ChemSol1.0 by Jan FLorian and Arieh Warshel calculates
solvation energies of compounds with partial charges calculated with
Gaussian (Florian & Warshel, J.Phys.Chem. B 1997).

For more recent papers on LRA, binding, redox, pka, reorganization of Warshels
group, please see for instance:

F. Lee et al. Prot.Eng. (1992)
F. Lee et al. J.Comp.Chem. (1993)
I Muegge et al. Structure (1996)
YY Sham et al. J.Phys.Chem. B (1997)
A Warshel et al. J.Biol.Inorg.Chem. (1997)
I Muegge et al. J.Phys.Chem. B (1997)
I Muegge et al. Prot.Eng. (12/1997) (should be out next month)
I Muegge et al. Proteins (3/1998) (should be out next month)
YY Sham et al. Biophysical J. (4/1998) (nshould be out in 2 month)

Best regards,
Ingo

--
Ingo Muegge
D-47E, AP10 2fl
Abbott Laboratories
100 Abbott Park Road
Abbott Park, IL 60064-3500

Phone: 847 935-4659
FAX: 847 937-2625
[email-masked]

-------------------------- reply 3 -------------------------------

In addition to the names you mentioned, I know that Mike K Gilson at
NIST has been considering these issues.

Bear

^[[7m^[[5mSOARING BEAR^[[0m   [email-masked]        O-topoisomerase
Computational Medicinal Chemistry            5'*:        :*.*
Cancer Biochemistry & Drug Design              |'*.    .*'| |
Protein & DNA Structural Biology               | | *.,* | | |
  currently seeking employment               3'*.DNA helix| *
http://ellington.pharm.arizona.edu/~bear         '***'  '**'

-------------------------- reply 4 -------------------------------

Dear Dr. Kirma,

        MD using FDPB solvent has been done and partially reported by
Mike Gilson and myself.  Initial results were reported in
J. Comp. Chem. in 1996.  Additional results are current being
written.  If you have further questions please send them to me.  The
calculations you want to do can be done using the program UHBD.

                Best Regards,

                        Jeffry

     Department of Biochemistry & Chemistry
     Duquesne University
     600 Forbes Ave.
     Pittsburgh, PA 15282-1530

     Phone:  (412) 396-4129
     FAX:      (412) 396-5683

     e-mail: [email-masked]

-------------------------- reply 5 -------------------------------

Dear Roy,

maybe the following paper is of interest for you:

Loeffler, Schreiber and Steinhauser; Calculation of the Dielectric Properties
of a Protein and its Solvent: Theory and Case Study. J Mol Biol 270, 520-534
(1997).

A recent paper about salt-link studies by MDS is:

Lounnas and Wade, Biochemistry (1997).

Regards,

Roger

--
Roger Abseher, PhD
EMBL, Meyerhofstrasse 1
D-69117 Heidelberg, Germany
Room No.: V115
Email: [email-masked]
Voice: +49 6221 387 305
Fax: +49 6221 387 517

-------------------------- reply 6 -------------------------------

        See works by Toshiko Ichiye et al. over the last 7
        years (Biophys J.,Biochemistry, Proteins)
        where we calculated electrostatic potentials at
        redox site in Fe-S proteins using simple coulombic
        representations (vis-a-vis Warshel) but without
        limiting solvent to grid-based dipoles.

        Swartz, Beck, Ichiye (1996) Dec. Biophys. J.
        Yelle, Park, Ichiye (1993,1995) Proteins.
        Swartz, Ichiye (1996,1997) Biochemistry.

        -Brian
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-------------------------- reply 7 -------------------------------

I have also to point out that Warshel has an All Atom model that
includes this effect.  You can look at:

Polarization Constraints in Molecular Dynamics Simulation of Aqueous
Solutions: the Surface Constraint All Atom Solvent (SCAAS)
 Model, A. Warshel and G. King, Chem. Phys. Lett. 121, 124 (1985)

or

Microscopic Models for Quantum Mechanical Calculations of Chemical
Processes in Solutions: LD/AMPAC and SCAAS/AMPAC
 Calculations of Solvation Energies. V. Luzhkov and A. Warshel, J. Comp.
Chem. 13, 199 (1992)

With my best wishes,

Jordi
--
Jordi Villa
Department of Chemistry
University of Minnesota
207 Pleasant St. SE
55455 Minneapolis MN
Tlf: 612-625-53 11   Fax: 612-626-9390
http://klingon.uab.es/jordi         e-mail:  [email-masked]