Force Fields for Small Molecules.

Abstract

Molecular dynamics (MD) simulations have been widely applied to computer-aided drug design (CADD). While MD has been used in a variety of applications such as free energy perturbation and long-time simulations, the accuracy of the results from those methods depends strongly on the force field used. Force fields for small molecules are crucial, as they not only serve as building blocks for developing force fields for larger biomolecules but also act as model compounds that will be transferred to ligands used in CADD. Currently, a wide range of small molecule force fields based on additive or nonpolarizable models have been developed. While these nonpolarizable force fields can produce reasonable estimations of physical properties and have shown success in a variety of systems, there is still room for improvements due to inherent limitations in these models including the lack of an electronic polarization response. For this reason, incorporating polarization effects into the energy function underlying a force field is believed to be an important step forward, giving rise to the development of polarizable force fields. Recent simulations of biological systems have indicated that polarizable force fields are able to provide a better physical representation of intermolecular interactions and, in many cases, better agreement with experimental properties than nonpolarizable, additive force fields. Therefore, this chapter focuses on the development of small molecule force fields with emphasis on polarizable models. It begins with a brief introduction on the importance of small molecule force fields and their evolution from additive to polarizable force fields. Emphasis is placed on the additive CHARMM General Force Field and the polarizable force field based on the classical Drude oscillator. The theory for the Drude polarizable force field and results for small molecules are presented showing their improvements over the additive model. The potential importance of polarization for their application in a wide range of biological systems including CADD is then discussed.