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