WHEN ARE FREE-ENERGY COMPONENTS MEANINGFUL

A method is proposed for estimating when free energy differences, as d etermined by computer simulation, may be decomposed in a meaningful wa y into components corresponding to either force field terms or groups of atoms. The method is applied to the determination of the solvation free energy difference between p-cyanophenol and p-methoxyphenol in aq ueous solution. For this system, a strong coupling is observed between the van der Waals and electrostatic interaction terms, which suggests that their relative contribution to the overall free energy change is dependent on the path between the two states and should therefore be interpreted with care. It is argued that this type of coupling between components will be present in most chemical and biological systems.