Pairwise-additive and polarizable atomistic force fields for molecular dynamics simulations of proteins

Protein force fields have been undergoing continual development since the first complete parameter sets were introduced nearly four decades ago. The functional forms that underlie these models have many common elements for the treatment of bonded and nonbonded forces, which are reviewed here. The most widely used force fields to date use a fixed-charge convention in which electronic polarization effects are treated via a mean-field approximation during partial charge assignment. Despite success in modeling folded proteins over many years, the fixed-charge assumption has limitations that cannot necessarily be overcome within their potential energy equations. To overcome these limitations, several force fields have recently been derived that explicitly treat electronic polarization effects with straightforward extensions of the potential energy functions used by nonpolarizable force fields. Here, we review the history of the most popular nonpolarizable force fields (AMBER, CHARMM, OPLS, and GROMOS) as well as studies that have validated them and applied them to studies of protein folding and misfolding. Building upon these force fields are more recent polarizable interaction potentials, including fluctuating charge models, POSSIM, AMOEBA, and the classical Drude oscillator. These force fields differ in their implementations but all attempt to model electronic polarization in a computationally tractable manner. Despite their recent emergence in the field of protein folding, several studies have already applied these polarizable models to challenging problems in this domain, including the role of polarization in folding free energies and sequence-specific effects on the stability of α-helical structures.