Peptide Conformational Equilibria Computed via a Single-Stage Shifting Protocol

Abstract

We study the conformational equilibria of two peptides using a novel statistical mechanics approach designed for calculating free energy differences between highly dis-similar conformational states. Our results elucidate the contrasting roles of entropy in implicitly solvated leucine dipeptide and decaglycine. The method extends earlier work by Voter, and overcomes the notorious "overlap" problem in free energy computations by constructing a mathematically equivalent calculation with high conformational similarity. The approach requires only equilibrium simulations of the two states of interest, without the need for sampling transition states. We discuss extensions of the approach to binding affinity estimation and explicitly solvated systems, as well as possible optimizations.