Conformational analysis of thiopeptides: Free energy calculations on the effects of thio-substitutions on the conformational distributions of alanine dipeptides

Abstract

When the oxygen atom in a peptide bond is replaced by a sulfur atom, the restriction in the available conformational space and the ability of thioamides to confer resistance to enzymatic degradation renders thioamides as potentially useful building blocks for drug design and protein engineering. The solvation free energy differences between conformers of the same dipeptide can be high. Yet, previous conformational studies, basing on the (φ,ψ) conformational energy maps of thio-substituted dipeptides, neglected both explicit water interactions and free energy considerations. In this paper, the (φ,ψ) conformational free energy maps are obtained by single umbrella sampling in an explicit water ..