We introduce the Open Force Field (OpenFF) 2.0.0 small
molecule
force field for drug-like molecules, code-named Sage, which builds
upon our previous iteration, Parsley. OpenFF force fields are based
on direct chemical perception, which generalizes easily to highly
diverse sets of chemistries based on substructure queries. Like the
previous OpenFF iterations, the Sage generation of OpenFF force fields
was validated in protein–ligand simulations to be compatible
with AMBER biopolymer force fields. In this work, we detail the methodology
used to develop this force field, as well as the innovations and improvements
introduced since the release of Parsley 1.0.0. One particularly significant
feature of Sage is a set of improved Lennard-Jones (LJ) parameters
retrained against condensed phase mixture data, the first refit of
LJ parameters in the OpenFF small molecule force field line. Sage
also includes valence parameters refit to a larger database of quantum
chemical calculations than previous versions, as well as improvements
in how this fitting is performed. Force field benchmarks show improvements
in general metrics of performance against quantum chemistry reference
data such as root-mean-square deviations (RMSD) of optimized conformer
geometries, torsion fingerprint deviations (TFD), and improved relative
conformer energetics (ΔΔE). We present
a variety of benchmarks for these metrics against our previous force
fields as well as in some cases other small molecule force fields.
Sage also demonstrates improved performance in estimating physical
properties, including comparison against experimental data from various
thermodynamic databases for small molecule properties such as ΔHmix, ρ(x), ΔGsolv, and ΔGtrans. Additionally, we benchmarked against protein–ligand binding
free energies (ΔGbind), where Sage
yields results statistically similar to previous force fields. All
the data is made publicly available along with complete details on
how to reproduce the training results athttps://github.com/openforcefield/openff-sage.