molecular rearrangement 183Molecular Modeling
by Karl F. Moschner, Ph.D.
Models, representations of real objects, have long been
used to understand, explain, predict, and, ultimately, har-
ness and exploit natural phenomena. They range from sim-
ple descriptions or drawings useful for conveying basic
concepts to precise mathematical relationships that can be
embodied in sophisticated computer programs. Whatever
their form, all models are approximations with individual
strengths and limitations that must be astutely applied to
solve particular problems quickly and properly.
Molecular modeling deals with the representation
and prediction of structures, properties, interactions, and
reactions of chemical substances. It is intimately linked
with experimental investigations of atomic and molecular
structure and determinations of physical, chemical, and
biological properties; mathematics (including statistics);
and computer science and graphics. At its heart is the
representation of molecular structure and interactions,
especially chemical bonding. Modern molecular modeling
has many uses as an effective communication tool, as a
means of simulating chemical phenomena that are difficult
or impossible to observe experimentally, and, ultimately,
as a means of designing new compounds and materials.
Chemists have historically employed various means of
representating molecular structure. Two-dimensional draw-
ings of atoms connected by lines are some of the most com-
mon molecular representations. Each line represents a
chemical bond that, in the simplest case, is a pair of elec-
trons shared between the connected atoms, resulting in a
very strong attractive interatomic force. The various inter-
atomic forces define the structure or shape of a molecule,
while its chemistry is dependent on the distribution of elec-
trons. A chemical reaction involves a change in the electron
distribution, i.e., a change in bonding.
X-ray crystallographic studies demonstrated that bond
distances are very uniform and that the three-dimensional
arrangements of atoms in a molecule have well-defined
geometries. The regularity in molecular structures made it
possible to build scale models about 250 million times larger
than the molecule. Some of the earliest molecular scale
models used standard atom-type wooden balls with holes at
appropriate angles that could be connected by ideal bond-
length sticks or springs. Such simple models were often a
chemist’s first opportunity to “see” a molecule, i.e., to
develop a concept of its shape or conformation.
Molecular scale models of various types served as
important tools for chemists. LINUSPAULINGwas a propo-
nent for using molecular scale models to better under-
stand the critical influence of three-dimensional structure
on molecular properties and reactivities, and models
helped Francis Crick and James Watson to elucidate the
double helical structure of DNA (WATSON-CRICK MODEL). But
they were awkward, fragile, and costly and offered only
limited structural information. Indeed, they failed to provide
any means of quantitatively comparing conformations of
flexible molecules, interactions between molecules, or
chemical reactivities. During the second half of the 20th
century, chemists sought to address these needs by taking
advantage of theoretical advances and emerging computer
technology to develop two general approaches to compu-
tational molecular modeling based on molecular mechan-
ics (MM) and quantum mechanics (QM).
Molecular mechanics computes molecular potential
energy using a force field, a series of discrete mathemati-
cal functions that reflect measurable intra- and inter-
molecular forces. In a manner similar to molecular scale
models, MM employs “ideal” atom- and bond-types. Dis-
tances are based principally on X-ray crystal structures,
and forces are derived from vibrational spectra. MM com-
puter programs (e.g., MM2, MM3, SYBYL, CHARMM, and
MACROMODEL) are differentiated by the range and speci-
ficity of their atom types, the mathematical expressions in
their force fields, and their treatment of nonbonding inter-
actions, including electrostatics, hydrogen-bonding, van
der Waals forces, and solvation. Some force fields haveMolecular model of an unidentified chemical. Its atoms
(spheres) interact to form chemical bonds (rods) that hold
the molecule together.(Courtesy of Lawrence Lawry/
Science Photo Library)(continues)