The accuracy of classical molecular mechanics (MM) force fields used for condensed phase molecular simulations depends strongly on the accuracy of modeling nonbonded interactions between atoms, such as electrostatic interactions.  Many current MM force fields use partial atomic charges derived from gas phase quantum chemistry calculations using the Hartree-Fock method with the relatively small 6-31G* basis set (HF/6-31G*).  It is generally believed that HF/6-31G* generates fortuitously overpolarized electron distributions, as would be expected in the higher dielectric environment of the condensed phase. Using a benchmark set of 46 molecules we show that HF/6-31G* does not uniformly overpolarize molecules and in some cases even leads to molecular dipole moments that are lower than experimental gas phase measurements.  We further demonstrate that using a more advanced quantum chemistry method, together with an appropriate augmented basis set and continuum solvent model, yields molecular dipole moments that are more uniformly overpolarized.  These data suggest that this method – or one similar to it – should be adopted for the derivation of accurate partial atomic charges for MM force fields.

Benchmarking quantum chemistry methods for accurate fixed-charge electrostatic models

2019 Fall National Meeting

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