The development of accurate transferable force fields
is key to
realizing the full potential of atomistic modeling in the study of
biological processes such as protein–ligand binding for drug
discovery. State-of-the-art transferable force fields, such as those
produced by the Open Force Field Initiative, use modern software engineering
and automation techniques to yield accuracy improvements. However,
force field torsion parameters, which must account for many stereoelectronic
and steric effects, are considered to be less transferable than other
force field parameters and are therefore often targets for bespoke
parametrization. Here, we present the Open Force Field QCSubmit and
BespokeFit software packages that, when combined, facilitate the fitting
of torsion parameters to quantum mechanical reference data at scale.
We demonstrate the use of QCSubmit for simplifying the process of
creating and archiving large numbers of quantum chemical calculations,
by generating a dataset of 671 torsion scans for druglike fragments.
We use BespokeFit to derive individual torsion parameters for each
of these molecules, thereby reducing the root-mean-square error in
the potential energy surface from 1.1 kcal/mol, using the original
transferable force field, to 0.4 kcal/mol using the bespoke version.
Furthermore, we employ the bespoke force fields to compute the relative
binding free energies of a congeneric series of inhibitors of the
TYK2 protein, and demonstrate further improvements in accuracy, compared
to the base force field (MUE reduced from 0.560.39
0.77 to 0.420.28
0.59 kcal/mol and R
2 correlation improved from 0.720.35
0.87 to 0.930.84
0.97).