*University of South Alabama, Department of Chemistry, Mobile,
Alabama 36688
a Bristol Myers-Squibb Pharmaceutical Research Institute,
P.O. Box 4000, Princeton, New Jersey 08543
b University of Houston, Department of Chemistry,Houston,
Texas 77204
and c European Molecular Biology Laboratory, Meyerhofstrasse
1, 6900 Heidelberg, Germany
Introduction:
Large biological molecules, such as superoxide dismutase (SOD), triose phosphate isomerase (TIM), acetylcholinesterase, rhinovirus, bacteriorhodopsin, antibodies, RNA, and DNA, have become accessible to theoretical study recently as a result of the availability of modern computers and sophisticated theories.. Two rapidly emerging areas of interest are the computation of electrostatic interactions using continuum models-5 and the simulation of diffusional motion in biopolymers and the diffusional encounters between ligands and their receptors based on Brownian dynamics. With continuum electrostatic methods, one is able to calculate accurate electrostatic energies and forces for ionizable groups in small molecules and biopolymers, determine accurate electrostatic free energies of salvation, and compute relative electrostatic free energies of binding. Brownian dynamics, on the other hand, extends the time frame for studying motions in enzymes, e.g., loop movements and hinge-bending motion. One can now begin to investigate motions that are in the nanosecond-to-microsecond range. Brownian dynamics coupled with continuum electrostatics can be used to understand the effects of electrostatics on the rate at which a substrate approaches a target enzyme. This has proven to be a valuable approach in the design of mutants of superoxide dismutase, which have increased catalytic activities.
Comp. Chem. Rev. (1994) 5, 229-267.