Estimating relative free energies from a single ensemble: Hydration free energies

The ability to determine the free energy of solvation for a number of small organic molecules with varying sizes and properties from the coordinate tr ajectory of a single simulation of a given reference state was investigated The relative free energies were estimated from a single step perturbation using the perturbation formula. The reference state consisted of a cavity s urrounded by solvent. To enhance sampling a soft-core interaction was used for the cavity. The effect of the size of the cavity, the effective core he ight, and the length of simulation on the ability to reproduce results obta ined from thermodynamic integration calculations was considered. The result s using a single step perturbation from an appropriately chosen initial sta te were comparable to results from thermodynamic integration calculations f or a wide range of compounds. Using a large number of compounds the computa tional efficiency was potentially increased by 2-3 orders of magnitude over traditional free energy approaches. Factors determining the efficiency of the approach are discussed. (C) 1999 John Wiley & Sons, Inc.