Peptide-Based Drug Design

116 Copps et al.
Fig. 1. Potential energy function for general class I force field.
shown in Fig. 1(1). In class I empirical force fields, bond stretching and angle
bending relative to equilibrium radius and angle values are described by the
classical, not quantum harmonic oscillator function, necessitating the use of
constraints to approximate the quantum effects of vibrating bonds and bond
angles. Bond rotation is described by a sinusoidal function that approximates the
peak energy from repulsion when a torsional angle is in the cis configuration, and
the minimum when it is in trans configuration. Finally, nonbonded interactions
are described by Lennard-Jones as well as Coulombic potentials, which approximate
the long-range forces between uncharged and charged atoms, respectively.
However, they overestimate the effect of molecular dipoles and cannot simulate
molecules with significantly different polar attributes simultaneously, and this
affects real equilibrium distance values because of the movement of atoms based
on polarization. Class I force fields also cannot compute properties which are far
from equilibrium or accurately predict vibrational spectra and they are temperature
dependent. Class II empirical force fields approximate the forces upon
molecules using more descriptive, complicated functions, such as using a Morse
potential in place of the harmonic oscillator in describing bond stretching and
angle bending, and higher-order terms in describing nonbonded interactions.
This increases the accuracy of prediction, but also increases the computation
time, often prohibitively.
The choice of a particular force field depends on the type of system for
which it has been designed. Several class I force fields have been designed for
description of polypeptides, including AMBER (2), CHARMM (3), OPLSand
OPLS-AA (4,5), and GROMOS96 (1). The computational study of peptides
and proteins can yield information regarding the importance of residues and
functional groups in determining the structure, folding and solubility in various
environments. This information can then be applied to the study of the structureactivity
relationships of those molecules in ligand–receptor complexes and aid
in the design of new therapeutics.