Using non-Gaussian density functional fits to improve relative free energy calculations.

The accurate and reliable computation of relative free energy differences remains an important long-term goal. Major stumbling blocks for achieving this goal reflect the difficulty of sampling in a known fashion along the reaction coordinate and of maximally combining information that has been collected from the simulation along the reaction coordinate. In this paper we examine the utility of a probability density functional type fit to the distribution of work events collected during a nonequilibrium sample along the reaction coordinate.

Using overlap and funnel sampling to obtain accurate free energies from nonequilibrium work measurements.

Two concepts are presented for accurate nonequilibrium work free-energy measurements, realized both in molecular simulation and experiment. First, the need for an intermediate important to both the reference and the target systems (overlap) is indicated. Second, the use of a soft path from each end point to the intermediate (funnel) is demonstrated.

Tools for channels: moving towards molecular calculations of gating and permeation in ion channel biophysics.

Recent X-ray structures of voltage gated potassium channels provide an exciting opportunity to connect molecular structures with measured biological function. Two of the most important connections for these channels are: first, to the molecular basis behind selectivity and the associated free energy profile underlying ionic current flow and, second, to a true molecular understanding of the large-scale conformational transitions that underlie voltage dependent gating. But, existing computational tools need to be further developed to reach these goals.

Improving the efficiency and reliability of free energy perturbation calculations using overlap sampling methods.

A challenge in free energy calculation for complex molecular systems by computer simulation is to obtain a reliable estimate within feasible computational time. In this study, we suggest an answer to this challenge by exploring a simple method, overlap sampling (OS), for producing reliable free-energy results in an efficient way. The formalism of the OS method is based on ensuring sampling of important overlapping phase space during perturbation calculations.

Variational formula for the free energy based on incomplete sampling in a molecular simulation.

Finite sampling in free-energy perturbation (FEP) calculations by molecular simulation leads to reproducible systematic errors, with sign shown to depend (in a known way) only on which system governs sampling in the simulation. Thus the result of a FEP calculation can be used as a bound on the true free energy. This inequality is of a wholly different nature from established forms such as the Gibbs-Bogoliubov inequality or the second law, in that its origins relate to the performance of a molecular simulation.