Benchmarking Force Field and the ANI Neural Network Potentials for the Torsional Potential Energy Surface of Biaryl Drug Fragments

Many drug molecules contain biaryl fragments, resulting in a torsional barrier corresponding to rotation around the bond linking the aryls. The potential energy surfaces of these torsions vary significantly because of steric and electronic effects, ultimately affecting the relative stability of the molecular conformations in the protein-bound and solution states. Simulations of protein-ligand binding require accurate computational models to represent the intramolecular interactions to provide accurate predictions of the structure and dynamics of binding. In this article, we compare four force fields [generalized AMBER force field (GAFF), open force field (OpenFF), CHARMM general force field (CGenFF), optimized potentials for liquid simulations (OPLS)] and two neural network potentials (ANI-2x and ANI-1ccx) for their ability to predict the torsional potential energy surfaces of 88 biaryls extracted from drug fragments. The root mean square deviation (rmsd) over the full potential energy surface and the mean absolute deviation of the torsion rotational barrier height (MADB) relative to high-level ab initio reference data (CCSD(T1)*) were used as the measure of accuracy. Uncertainties in these metrics due to the composition of the data set were estimated using bootstrap analysis. In comparison to high-level ab initio data, ANI-1ccx was most accurate for predicting the barrier height (rmsd: 0.5 +/- 0.0 kcal/mol, MADB: 0.8 +/- 0.1 kcal/mol), followed closely by ANI-2x (rmsd: 0.5 +/- 0.0 kcal/mol, MADB: 1.0 +/- 0.2 kcal/mol), then CGenFF (rmsd: 0.8 +/- 0.1 kcal/mol, MADB: 1.3 +/- 0.1 kcal/mol) and OpenFF (rmsd: 0.7 +/- 0.1 kcal/mol, MADB: 1.3 +/- 0.1 kcal/mol), then GAFF (rmsd: 1.2 +/- 0.2 kcal/mol, MADB: 2.6 +/- 0.5 kcal/mol), and finally OPLS (rmsd: 3.6 +/- 0.3 kcal/mol, MADB: 3.6 +/- 0.3 kcal/mol). Significantly, the neural network potentials (NNPs) are systematically more accurate and more reliable than any of the force fields. As a practical example, the NNP/molecular mechanics method was used to simulate the isomerization of ozanimod, a drug used for multiple sclerosis. Multinanosecond molecular dynamics (MD) simulations in an explicit aqueous solvent were performed, as well as umbrella sampling and adaptive biasing force-enhanced sampling techniques. The rate constant for this isomerization calculated using transition state theory was 4.30 x 10(-1) ns(-1), which is consistent with direct MD simulations.