Theoretically grounded approaches to account for polarization effects in fixed-charge force fields.

Abstract

Non-polarizable, or fixed-charge, force fields are the workhorses of most molecular simulation studies. They attempt to describe the potential energy surface (PES) of the system by including polarization effects in an implicit way. This has historically been done in a rather empirical and ad hoc manner. Recent theoretical treatments of polarization, however, offer promise for getting the most out of fixed-charge force fields by judicious choice of parameters (most significantly the net charge or dipole moment of the model) and application of post facto polarization corrections. This Perspective describes these polarization theories, namely the "halfway-charge" theory and the molecular dynamics in electronic continuum theory, and shows that they lead to qualitatively (and often, quantitatively) similar predictions. Moreover, they can be reconciled into a unified approach to construct a force field development workflow that can yield non-polarizable models with charge/dipole values that provide an optimal description of the PES. Several applications of this approach are reviewed, and avenues for future research are proposed.