General Model for Treating Short-Range Electrostatic Penetration in a Molecular Mechanics Force Field

[Image: see text] Classical molecular mechanics force fields typically model interatomic electrostatic interactions with point charges or multipole expansions, which can fail for atoms in close contact due to the lack of a description of penetration effects between their electron clouds. These short-range penetration effects can be significant and are essential for accurate modeling of intermolecular interactions. In this work we report parametrization of an empirical charge–charge function previously reported ( J.-P. Piquemal; J. Phys. Chem. A2003, 107, 1035326313624) to correct for the missing penetration term in standard molecular mechanics force fields. For this purpose, we have developed a database (S101×7) of 101 unique molecular dimers, each at 7 different intermolecular distances. Electrostatic, induction/polarization, repulsion, and dispersion energies, as well as the total interaction energy for each complex in the database are calculated using the SAPT2+ method ( T. M. Parker; J. Chem. Phys.2014, 140, 09410624606352). This empirical penetration model significantly improves agreement between point multipole and quantum mechanical electrostatic energies across the set of dimers and distances, while using only a limited set of parameters for each chemical element. Given the simplicity and effectiveness of the model, we expect the electrostatic penetration correction will become a standard component of future molecular mechanics force fields.