Absolute Free-Energy Calculations of Liquids Using a Harmonic Reference State

Abstract

Absolute free-energy methods provide a potential solution to the overlap problem in free-energy calculations. In this paper, we report an extension of the previously published confinement method (J. Phys. Chem. B 2006, 110, 17212-20) to fluid simulations. Absolute free energies of liquid argon and liquid water are obtained accurately and compared with results from thermodynamic integration. The method works by transforming the liquid state into a harmonic, solid reference state. This is achieved using a special restraint potential that allows molecules to change their restraint position during the simulation, which circumvents the need for the molecules to sample the full extent of their translational freedom. The absolute free energy of the completely restrained reference state is obtained from a normal mode calculation. Because of the generic reference state used, the method is applicable to nonhomogeneous, diffusive systems and could provide an alternative method in situations in which solute annihilation fails due to the size of the solute. Potential applications include calculation of solvation energies of large molecules and free energies of peptide conformational changes in explicit solvent.