Optimization and Automation of the Construction of Smooth Free Energy Profiles

An adaptive procedure is introduced to construct smooth analytical profiles of the free energy along a reaction coordinate using sampled data from multiple biased simulations. The procedure is based upon identifying problematic regions encountered in maximum likelihood estimators of the profile where there are statistically relevant discrepancies between the empirical and parametrized cumulative distribution functions and preferentially improving the construction of the parametric profile in these regions. The method is designed to produce continuous and smooth analytical fits that satisfy statistical goodness-of-fit tests with a minimum number of parameters. The accuracy of the profile obtained from the adaptive construction is compared by numerical computation to that of smooth interpolations based on an optimally chosen weighted histogram method for a solvated ion pair system and for an activated process for which the analytical form of the potential of mean force is available. In the model where the exact profile is known, the adaptive procedure is shown to reduce the integrated error relative to the optimal histogram construction by a factor of 3 or more in the typical case where the sampling is not extensive. It is demonstrated that the adaptive procedure can be used to produce statistically accurate smooth analytical representations of the free energy profile that can be evaluated with little computational effort and require little user input.