Application of the multiensemble sampling to the hydration free energy

We demonstrate the feasibility of using multiensemble sampling method (MESM ) to determine the free energy difference between two far states for which the configurational distributions do not overlap at all. The MESM is a rece ntly developed non-Boltzmann sampling technique. The free energy of chargin g a sodium ion in water is accurately calculated in a single simulation, in troducing nine intermediate ionic states. This is due to the ability of the method to explore the relevant parts of configuration space equally for ev ery state, and this ability comes from the universality of weighting functi on W and the simplicity in adjusting its parameters. Detailed procedures of adjusting the parameters are presented. The comparison with a free energy perturbation method (FEPM) shows that the MESM is more reliable and efficie nt. (C) 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1004-1009, 2001.