  We have developed a new simulation algorithm for free-energy calculations.
The method is a multidimensional extension of the replica-exchange method.
While pairs of replicas with different temperatures are exchanged during the
simulation in the original replica-exchange method, pairs of replicas with
different temperatures and/or different parameters of the potential energy are
exchanged in the new algorithm. This greatly enhances the sampling of the
conformational space and allows accurate calculations of free energy in a wide
temperature range from a single simulation run, using the weighted histogram
analysis method.
