Prediction of hydration free energies for aliphatic and aromatic chloro derivatives using molecular dynamics simulations with the OPLS-AA force field

All-atom molecular dynamics computer simulations were used to blindly predict the hydration free energies of a range of chloro-organic compounds as part of the SAMPL3 challenge. All compounds were parameterized within the framework of the OPLS-AA force field, using an established protocol to compute the absolute hydration free energy via a windowed free energy perturbation approach and thermodynamic integration. Three different approaches to deriving partial charge parameters were pursued: (1) using existing OPLS-AA atom types and charges with minor adjustments of partial charges on equivalent connecting atoms; (2) calculation of quantum mechanical charges via geometry optimization, followed by electrostatic potential (ESP) fitting, using Jaguar at the LMP2/cc-pVTZ(-F) level; and (3) via geometry optimization and CHelpG charges (Gaussian03 at the HF/6-31G* level), followed by two-stage RESP fitting. Protocol 3 generated the most accurate predictions with a root mean square (RMS) error of for the entire data set. It was found that the deficiency of the standard OPLS-AA parameters, protocol 1 (RMS error overall), was mostly due to compounds with more than three chlorine substituents on an aromatic ring. For this latter subset, the RMS errors were (protocol 3) and (protocol 1), respectively. We propose new OPLS-AA atom types for aromatic carbon and chlorine atoms in rings with a parts per thousand yen4 Cl-substituents that perform better than the best QM-based approach, resulting in an RMS error of for these difficult compounds.