Development and Comprehensive Benchmark of a High Quality AMBER-Consistent Small Molecule Force Field with Broad Chemical Space Coverage for Molecular Modeling and Free Energy Calculation

Biomolecular simulations have become an essential tool in contemporary drug discovery and molecular mechanics force fields constitute its cornerstone. Developing a high quality and broad coverage general force field is a significant undertaking that requires substantial expert knowledge and computing resources, which is beyond the scope of general practitioners. Existing force fields originate from only a limited number of groups and organizations, and they either suffer from limited numbers of training sets, lower than desired quality because of oversimplified representations, or are costly for the molecular modeling community to access. To address these issues, in this work, we developed an AMBER-consistent small molecule force field with extensive chemical space coverage and we provide Open Access parameters for the entire modeling community. To validate our force field, we carried out benchmarks of quantum mechanics/molecular mechanics conformer comparison and free energy perturbation calculations on several benchmark data sets. Our force field achieves a higher level performance at reproducing quantum mechanics energies and geometries than two popular open-source force fields, OpenFF2 and GAFF2. In relative binding free energy calculations for 31 protein-ligand data sets, comprising 1079 pairs of ligands, the new force field achieves an overall root mean square error of 1.19 kcal/mol for ∆∆G and 0.92 kcal/mol for ∆G on a subset of 463 ligands without bespoke fitting to the data sets. The results are on par with the leading commercial series of OPLS force fields.