Predictions of hydration free energies from continuum solvent with solute polarizable models: the SAMPL2 blind challenge

This paper reports the results of our attempt to predict hydration free energies on the SAMPL2 blind challenge dataset. We mostly examine the effects of the solute electrostatic component on the accuracy of the predictions. The usefulness of electronic polarization in predicting hydration free energies is assessed by comparing the Electronic Polarization from Internal Continuum model and the self consistent reaction field IEF-PCM to standard non-polarizable charge models such as RESP and AM1-BCC. We also determine an optimal restraint weight for Dielectric-RESP atomic charges fitting. Statistical analysis of the results could not distinguish the methods from one another. The smallest average unsigned error obtained is 1.9 ± 0.6 kcal/mol (95% confidence level). A class of outliers led us to investigate the importance of the solute–solvent instantaneous induction energy, a missing term in PB continuum models. We estimated values between −1.5 and −6 kcal/mol for a series of halo-benzenes which can explain why some predicted hydration energies of non-polar molecules significantly disagreed with experiment.