Thermodynamic Stability of β-Peptide Helices and the Role of Cyclic Residues

Beta-peptides are emerging as an attractive class of peptidomimetic molecules. In contrast to naturally occurring α-peptides, short oligomers of β-amino acids (comprising just 4–6 monomers) exhibit stable secondary structures that make them amenable for quantitative, concerted experimental and theoretical studies of the effects of particular chemical interactions on structure. In this work, molecular simulations are used to study the thermodynamic stability of helical conformations formed by β-peptides containing varying proportions of acyclic (β3) and cyclic (ACH) residues. More specifically, several β-peptides differing only in their content of cyclic residues are considered in this work. Previous computational studies of β-peptides have relied mostly on energy minimization of molecular dynamics simulations. In contrast, our study relies on density-of-states based Monte Carlo simulations to calculate the free energy and examine the stability of various folded structures of these molecules along a well-defined order parameter. By resorting to an expanded-ensemble formalism, we are able to determine the free energy required to unfold specific molecules, a quantity that could be measured directly through single-molecule force spectroscopy. Simulations in both implicit and explicit solvents have permitted a systematic study of the role of cyclic residues and electrostatics on the stability of secondary structures. The molecules considered in this work are shown to exhibit stable H-14 helical conformations and, in some cases, relatively stable H-12 conformations, thereby suggesting that solvent quality may be used to manipulate the hydrogen-bonding patterns and structure of these peptides.