Benchmark Assessment of Molecular Geometries and Energies from Small Molecule Force Fields

Force fields are used in a wide variety of contexts for classical molecular simulation, including studies on protein-ligand binding, membrane permeation, and thermophysical property prediction. The quality of these studies relies on the quality of the force fields used to represent the systems.

Focusing on small molecules of fewer than 50 heavy atoms, our aim in this work is to compare six force fields: GAFF, GAFF2, MMFF94, MMFF94S, SMIRNOFF99Frosst, and the Open Force Field version 1.0 (Parsley) force field. On a dataset comprising over 26,000 molecular structures, we analyzed their force field-optimized geometries and conformer energies compared to reference quantum mechanical (QM) data. We show that most of these force fields are comparable in accuracy at reproducing gas-phase QM geometries and energetics, but that GAFF/GAFF2/Parsley do slightly better in reproducing QM energies and that MMFF94/MMFF94S perform slightly better in geometries. Parsley shows considerable improvement over its predecessor SMIRNOFF99Frosst, and we identify particular outlying chemical groups for further force field improvement.