Biomolecular Force Field Parameterization via Atoms-in-Molecule Electron Density Partitioning

Molecular mechanics
force fields, which are commonly used in biomolecular
modeling and computer-aided drug design, typically treat nonbonded
interactions using a limited library of empirical parameters that
are developed for small molecules. This approach does not account
for polarization in larger molecules or proteins, and the parametrization
process is labor-intensive. Using linear-scaling density functional
theory and atoms-in-molecule electron density partitioning, environment-specific
charges and Lennard-Jones parameters are derived directly from quantum
mechanical calculations for use in biomolecular modeling of organic
and biomolecular systems. The proposed methods significantly reduce
the number of empirical parameters needed to construct molecular mechanics
force fields, naturally include polarization effects in charge and
Lennard-Jones parameters, and scale well to systems comprised of thousands
of atoms, including proteins. The feasibility and benefits of this
approach are demonstrated by computing free energies of hydration,
properties of pure liquids, and the relative binding free energies
of indole and benzofuran to the L99A mutant of T4 lysozyme.