AN EXTENDED LINEAR-RESPONSE METHOD FOR DETERMINING FREE-ENERGIES OF HYDRATION

Fourteen neutral organic molecules with diverse functionalities have been used to determine the utility of equations based on linear response theory for the calculation of free energies of hydration. The equations contain terms proportional to the Coulombic and van der Waals components of the solute-solvent interaction energy and to an index for the cost of cavity formation such as solvent-accessible surface area. The energy components can be obtained from Monte Carlo or molecular dynamics simulations of the solutes in water. The methodology has been tested using partial charges from fitting to the electrostatic potentials of ab initio 6-31G* wave functions and from OPLS potential functions. Root-mean-square deviations between the results from the recommended linear response methods and experimental free energies of hydration are ca. 0.8 kcal/mol. Substituted benzenes, not included in the parameter development, have been used to further evaluate the method's performance.