What stabilizes the 3(14)-helix in beta3-peptides? A conformational analysis using molecular simulation

Beta-peptides are analogs of natural alpha-peptides and form a variety of remarkably stable structures. Having an additional carbon atom in the backbone of each residue, their folded conformation is not only influenced by the side-chain sequence but also and foremost by their substitution pattern. The precise mechanism by which the side chains interact with the backbone is, however, hitherto not completely known. To unravel the various effects by which the side chains influence the backbone conformation, we quantify to which extent the dihedral angles of a beta(3)-substituted peptide with an additional methyl group on the central C(alpha)-atom can be regarded as independent degrees of freedom and analyze the distributions of these dihedral angles. We also selectively capture the steric effect of substituents on the C(alpha)- and C(beta)-atoms of the central residue by alchemically changing them into dummy atoms, which have no nonbonded interactions. We find that the folded state of the beta(3)-peptide is primarily stabilized by a steric exclusion of large parts of the unfolded state (entropic effect) and only subsequently by mutual dependence of the psi-dihedral angles (enthalpic effect). The folded state of beta-peptides is stabilized by a different mechanism than that of alpha-peptides.