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 1.2 kcal mol^-1 for the entire data set. It was found that the deficiency of the standard OPLS-AA parameters, protocol 1 (RMS error 2.4 kcal moL^-1 overall), was mostly due to compounds with more than three chlorine substituents on an aromatic ring. For this latter subset, the RMS errors were 1.4 kcal mol^-1 (protocol 3) and 4.3 kcal moL ^-1 (protocol 1), respectively. We propose new OPLS-AA atom types for aromatic carbon and chlorine atoms in rings with ≥4 Cl-substituents that perform better than the best QM-based approach, resulting in an RMS error of 1.2 kcal mol^-1 for these difficult compounds.