Accuracy and convergence of free energy differences calculated from nonequilibrium switching processes

Abstract

The molecular-dynamics-based calculation of accurate free energy differences for biomolecular systems is a challenging task. Accordingly, convergence and accuracy of established equilibrium methods has been subject of many studies, often focusing at small test systems. In contrast, the potential of more recently proposed nonequilibrium methods, derived from the Jarzynski and Crooks equalities, has not yet fully been explored. Here, we compare the performance of these methods by calculating free energy differences for test systems at different levels of complexity and varying extent of the involved perturbations. We consider the interconversion of ethane into methanol, the switching of a tryptophane-sidechain in a tripeptide, and the binding of two different ligands to the globular protein snurportin 1. On the basis of our results, we suggest and assess a new nonequilibrium free energy method, Crooks Gaussian Intersection (CGI), which combines the advantages of existing methods. CGI is highly parallelizable and, for the test systems considered here, is shown to outperform the other studied equilibrium and nonequilibrium methods.