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

preprint
revised on 13.08.2020 and posted on 13.08.2020 by Victoria T. Lim, David F. Hahn, Gary Tresadern, Christopher I. Bayly, David Mobley
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.

Funding

Alchemical free energy methods for efficient drug lead optimization

National Institute of General Medical Sciences

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Advancing predictive physical modeling through focused development of model systems to drive new modeling innovations

National Institute of General Medical Sciences

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Open data-driven infrastructure for building biomolecular force fields for predictive biophysics and drug design

National Institute of General Medical Sciences

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History

Email Address of Submitting Author

dmobley@uci.edu

Institution

University of California, Irvine

Country

United States

ORCID For Submitting Author

0000-0003-4030-9312

Declaration of Conflict of Interest

David Mobley serves on the Scientific Advisory Board of OpenEye Scientific Software and is an Open Science Fellow with Silicon Therapeutics

Version Notes

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

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