Solubility of organic compounds in water/octanol systems. A expanded ensemble molecular dynamics simulation study of log P parameters

The expanded ensemble method, developed to calculate solvation free energie s,, is applied to calculate octanol/water partition coefficients P for some organic drug-related molecules and compared with experimental results. The experimental log P results were obtained by a miniaturized vial procedure using liquid chromatography with UV for quantification, The expanded ensemb le technique, implemented within molecular dynamics scheme, is adapted to t reat molecules of arbitrary size and type. For octanol, both all-atom and u nited atom models are evaluated. The solvation free energy of the organic s olute molecules is found to be sensitive to the used sets of partial charge s on the atoms in polar groups, particularly in water but also in the satur ated octanol phase. Although this effect partially cancels out in the calcu lated partition coefficients, the charges obtained from ab initio Mulliken population analysis give consistently larger log P values than those obtain ed in simulations with the larger empirical atomic charges included in the CHARMM force field. In general, calculated log P turned out to be systemati cally higher than those measured experimentally. The possibility of improvi ng potential models for the solutes in water and oil phase, respectively, i s discussed.