A simple model for polyproline II structure in unfolded states of alanine-based peptides.

The striking similarity between observed circular dichroism spectra of nonprolyl homopolymers and that of regular left-handed polyproline II (P(II)) helices prompted Tiffany and Krimm to propose in 1968 that unordered peptides and unfolded proteins are built of P(II) segments linked by sharp bends. A large body of experimental evidence, accumulated over the past three decades, provides compelling evidence in support of the original hypothesis of Tiffany and Krimm. Of particular interest are the recent experiments of Shi et al. who find significant P(II) structure in a short unfolded alanine-based peptide. What is the physical basis for P(II) helices in peptide and protein unfolded states? The widely accepted view is that favorable chain-solvent hydrogen bonds lead to a preference for dynamical fluctuations about noncooperative P(II) helices in water. Is this preference simply a consequence of hydrogen bonding or is it a manifestation of a more general trend for unfolded states which are appropriately viewed as chains in a good solvent? The prevalence of closely packed interiors in folded proteins suggests that under conditions that favor folding, water-which is a better solvent for itself than for any polypeptide chain-expels the chain from its midst, thereby maximizing chain packing. Implicit in this view is a complementary idea: under conditions that favor unfolding, chain-solvent interactions are preferred and in a so-called good solvent, chain packing density is minimized. In this work we show that minimization of chain packing density leads to preferred fluctuations for short polyalanyl chains around canonical, noncooperative P(II)-like conformations. Minimization of chain packing is modeled using a purely repulsive soft-core potential between polypeptide atoms. Details of chain-solvent interactions are ignored. Remarkably, the simple model captures the essential physics behind the preference of short unfolded alanine-based peptides for P(II) helices. Our results are based on a detailed analysis of the potential energy landscape which determines the system's structural and thermodynamic preferences. We use the inherent structure formalism of Stillinger and Weber, according to which the energy landscape is partitioned into basins of attraction around local minima. We find that the landscape for the experimentally studied seven-residue alanine-based peptide is dominated by fluctuations about two noncooperative structures: the left-handed polyproline II helix and its symmetry mate.