Development and Benchmarking of Open Force Field 2.0.0: The Sage Small Molecule Force Field

We introduce the Open Force Field (OpenFF) 2.0.0 smallmoleculeforce field for drug-like molecules, code-named Sage, which buildsupon our previous iteration, Parsley. OpenFF force fields are basedon direct chemical perception, which generalizes easily to highlydiverse sets of chemistries based on substructure queries. Like theprevious OpenFF iterations, the Sage generation of OpenFF force fieldswas validated in protein-ligand simulations to be compatiblewith AMBER biopolymer force fields. In this work, we detail the methodologyused to develop this force field, as well as the innovations and improvementsintroduced since the release of Parsley 1.0.0. One particularly significantfeature of Sage is a set of improved Lennard-Jones (LJ) parametersretrained against condensed phase mixture data, the first refit ofLJ parameters in the OpenFF small molecule force field line. Sagealso includes valence parameters refit to a larger database of quantumchemical calculations than previous versions, as well as improvementsin how this fitting is performed. Force field benchmarks show improvementsin general metrics of performance against quantum chemistry referencedata such as root-mean-square deviations (RMSD) of optimized conformergeometries, torsion fingerprint deviations (TFD), and improved relativeconformer energetics (Delta Delta E). We presenta variety of benchmarks for these metrics against our previous forcefields as well as in some cases other small molecule force fields.Sage also demonstrates improved performance in estimating physicalproperties, including comparison against experimental data from variousthermodynamic databases for small molecule properties such as Delta H (mix), rho-(x), Delta G (solv), and Delta G (trans). Additionally, we benchmarked against protein-ligand bindingfree energies (Delta G (bind)), where Sageyields results statistically similar to previous force fields. Allthe data is made publicly available along with complete details onhow to reproduce the training results at https://github.com/openforcefield/openff-sage.

Automated summary

We introduce the OpenFF 2.0.0 small molecule force field Sage, an improved version of Parsley. It features improved LJ parameters and fitting to a larger database of quantum chemical calculations. Force field benchmarks show improved performance and estimation of physical properties. Complete data and training results are available at https://github.com/openforcefield/openff-sage.