Electronic polarization (or lack thereof) plays a large role in determining solvation free energies of small molecules in a highly polar solvent such as water. Although fixed-charge molecular mechanical force fields take account of polarization in an implicit manner, an explicit representation of polarization via the inclusion of induced dipoles at every atomic site may be expected to improve the accuracy of hydration free energy (HFE) predictions for drug-like molecules and fragments, with corresponding effects on other predictions such as binding free energies.We test this assertion by performing BAR HFE calculations using the AMOEBA polarizable force field on a benchmark set of 52 small molecules from the SAMPL4 HFE challenge. We demonstrate the use of the recently released Poltype program, developed by Ren and coworkers, to automatically generate parameters for the benchmark set consistent with the AMOEBA water model and wider force field. Our results using these parameters show good correlation and accuracy to experiment, and are compared with both fixed-charge MM based calculations and those adding a QM/MM-based representation of polarization contributions to the underlying MM force field.We then validate the automatic AMOEBA parameterization further by correlating AMOEBA electrostatic potentials and dipole moments with those of QM across the course of our simulations. This broad evaluation of the parameters during molecular dynamics goes beyond previous efforts to validate AMOEBA during its parameterization, and allows us to examine the performance of the Poltype approach in this context, focusing particularly on the conformational dependence of the electrostatics and polarization terms of the force field. Opportunities for improving automated parameter derivation are identified and discussed in light of these comparisons. Our findings should aid the wider application of the AMOEBA potential for other studies involving drug-like small molecules or fragments.

Evaluating automated small molecule parameter derivation for the AMOEBA polarizable force field

248th National Meeting (2014)

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