Free energies of solvation in chloroform and water from a linear response approach

Monte Carlo statistical mechanics simulations were used to compute absolute free energies of solvation in chloroform for 16 organic molecules. The intermolecular interactions were described by classical potential functions consisting of Coulomb and Lennard–Jones interactions. The partial charges for the solutes were derived from fitting to the electrostatic potential surfaces of ab initio 6–31G* wavefunctions. First, free energy perturbation (FEP) calculations yielded relative free energies of solvation. These were converted to absolute quantities through perturbations to the reference molecule, methane, which was annihilated. The average error in the FEP-computed free energies of solvation is 0·8 kcal mol−1. Then, a linear response equation, which contains terms proportional to the Lennard–Jones (van der Waals) and Coulombic components of the solute–solvent energy and to the solvent-accessible surface area of the solute, was optimized and reproduced both the FEP-calculated and experimental free energies of solvation with average errors of ca 0·5 kcal mol−1. In addition, an existing solute dataset for water, which had previously been fitted to the same equation, was expanded from 16 to 35 molecules. The fit of the Monte Carlo results for this set of molecules in TIP4P water to the experimental free energies of hydration yielded an average error of 0·8 kcal mol−1. Combination of the predictions of free energies of solvation in water and chloroform yields partition coefficients, log P, with an average error of 0·3–0·4 log unit. © 1997 John Wiley & Sons, Ltd.