Free Energies of Solvation in Cyclohexane and Water: United-Atom vs All-Atom.

Abstract

Free energies of solvation (ΔGsol) in a prototypical liquid alkane, cyclohexane, have been computed for 101 organic molecules at 25 °C. Monte Carlo statistical mechanics (MC) was used with free-energy perturbation theory (FEP) and both OPLS united-atom (UA) and all-atom (AA) force fields. Updated OPLS-UA parameters are provided along with thermodynamic results for 23 liquid alkanes; the modifications make the UA and AA force fields fully compatible. The average errors for ΔGsol in comparison to experimental data are ca. 0.5 kcal/mol for both force fields. This supports general use of the UA model, since it reduces the required computation times by 5-10-fold. The largest errors are about 1 kcal/mol and occur for small molecules with relatively large dipole moments and for perfluorocarbons. The former case is attributable to the lack of solvent-polarization in the force fields, and the latter issue can be remedied by reducing the Lennard-Jones well depth for the interaction of saturated carbon and fluorine. Results for free energies of hydration are also provided for the 101 solutes in TIP4P water and the average error is again 0.5 kcal/mol. The combined results provide cyclohexane/water free energies of transfer with average errors of 0.7 kcal/mol. In conjunction with prior results for solvation in benzene and perfluorobenzene, the 0.5 kcal/mol level of accuracy seems general for the performance of current generation, nonpolarizable force fields. Implications for modeling hydrophobic effects and protein-ligand binding are also considered.