Dissecting the Conformational Free Energy of a Small Peptide in Solution.

The free energy surface of a small peptide was analyzed based on an unbiased microsecond molecular dynamics simulation. The peptide sampled disordered conformational ensembles of distinct compactness, and its free energy was decomposed into separate contributions from the intramolecular potential energy, conformational entropy, and solvation free energy. The latter was further broken down into enthalpic and entropic contributions due to peptide-water and water-water interactions. This decomposition was enabled by a generalized linear response relation between the peptide-water interaction energy and the solvation free energy, which was empirically parametrized by explicit solvation free energy calculations for representative peptide conformations. This full dissection of the peptide free energy identifies individual contributions that stabilize and destabilize compact and extended peptide conformational ensembles and reveals the origin of a free energy barrier associated with transitions between them.