Theoretical and Computational Chemistry

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 nine force fields: GAFF, GAFF2, MMFF94, MMFF94S, OPLS3e, SMIRNOFF99Frosst, and the Open Force Field Parsley, versions 1.0, 1.1 and 1.2. On a dataset comprising 22,675 molecular structures of 3,271 molecules, we analyzed force field-optimized geometries and conformer energies compared these to reference quantum mechanical (QM) data. We show that while OPLS3e performs best, the latest Open Force Field Parsley release is approaching a comparable level of accuracy in reproducing QM geometries and energetics for this set of molecules. Meanwhile, the performance of established force fields such as MMFF94s and GAFF2 is generally somewhat worse. We also find that the series of recent Open Force Field versions provide significant increases in accuracy. Our molecule set and results are available for other researchers to use in testing.

Version notes

This relatively extensive update of our preprint adds benchmarking relative to several additional force fields.


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Supplementary material

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