Simulation ofβ-depsipeptides: The effect of missing hydrogen-bond donors on their folding equilibria

beta-Depsipeptides are beta-peptides in which one or more peptide linkages are replaced by ester linkages, resulting in a loss of a hydrogen-bond donor (N-H) and weakening of the corresponding carbonyl hydrogen-bond acceptor moiety. The effects of three of such peptide by ester substitutions in a hepta-beta-peptide upon its (un)folding equilibrium in methanol solution are investigated using molecular dynamics simulations and compared to experimental data from NMR spectroscopy. The simulated conformational ensembles largely reproduce the experimentally measured NOE and (3)J-coupling constant data for the three different hepta-beta-peptides, and confirm the relative stabilities of the 3(14)-helical conformation, which is most weakened by substitution of the 4th peptide linkage and least by substitution of the 6th peptide linkage. The simulations are complementary to the experimental data by providing detailed insight into the conformational distributions that are compatible with the experimentally measured average values of observables. (c) 2006 Wiley Periodicals, Inc.