Parametrization of Force Field Bonded Terms under Structural Inconsistency

Parametrization of the bonded part of molecular mechanics (MM) force fields (FFs) is typically done by fitting reference quantum mechanical (QM) energies or forces of representative structures. FFs for small molecules are constructed in incremental parametrization procedures, where parameters developed previously are retained for novel molecules, followed by optimization of missing, not previously optimized parameters. Equilibrium QM and MM geometries of molecules can deviate due to parameters transferred from existing molecules in the FF. In this work, we demonstrate that conventional parametrization methods based on fitting QM energies and/or forces to derive parameters for bond and angle terms produce largely suboptimal force constants when MM and QM equilibrium structures deviate. We further developed and tested a new method to derive CHARMM FF parameters based on the potential energy surface scans where a structural deviation between QM and MM optimized geometries is explicitly allowed during parametrization. The test of the new method was performed on a diverse set of 32 molecules. The results show that without any need for additional restraints, the new method produces robust and largely transferable parameters for bond and angle terms. The new method also improves the agreement for the normal modes for all molecules in the test set, reducing the average error in the reproduction of QM normal mode frequencies from 9.5% computed with CGenFF parameters to 6.8% computed with the new parameters. The new method will allow parametrization of molecules under structural deviations, common for force fields for small molecules, producing robust and transferable parameters.