A generalized linear response framework for expanded ensemble and replica exchange simulations

Expanded ensemble simulation is a powerful technique for enhancing sampling over a range of thermodynamic parameters. However, although the premise is relatively simple, running successful simulations in practice still presents something of an ad hoc challenge. Three main difficulties exist: (1) the selection of the thermodynamic states, (2) the selection of the sampling weights, and (3) efficient sampling of the expanded parameter space. Here we consider these problems in the context of a pairwise linear response approach to the work fluctuation theorem. The approach offers comprehensive tactics for addressing the three difficulties and can be used as either an alternative or a complement to replica exchange simulations. Importantly, the results are trivially implemented for multi-dimensional parameter spaces and they recover results from the literature aimed at the special cases of simulated/parallel tempering and replica exchange umbrella sampling. Illustrative examples are shown using the NAMD simulation engine.