Practical Considerations for Building GROMOS-Compatible Small-Molecule Topologies

Abstract

Molecular dynamics simulations are being applied to increasingly complex systems, including those involving small endogenous compounds and drug molecules. In order to obtain meaningful and accurate data from these simulations, high-quality topologies for small molecules must be generated in a manner that is consistent with the derivation of the force field applied to the system. Often, force fields are designed for use with macromolecules such as proteins, making their transferability to other species challenging. Investigators are increasingly attracted to automated topology generation programs, although the quality of the resulting topologies remains unknown. Here we assess the applicability of the popular PRODRG server that generates small-molecule topologies for use with the GROMOS family of force fields. We find that PRODRG does not reproduce topologies for even the most well-characterized species in the force field due to inconsistent charges and charge groups. We assessed the effects of PRODRG-derived charges on several systems: pure liquids, amino acids at a hydrophobic-hydrophilic interface, and an enzyme-cofactor complex. We found that partial atomic charges generated by PRODRG are largely incompatible with GROMOS force fields, and the behavior of these systems deviates substantially from that of simulations using GROMOS parameters. We conclude by proposing several points as "best practices" for parametrization of small molecules under the GROMOS force fields.