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1 Department of Biomedical Engineering and Center for Computational Biology, Washington University in St. Louis, St. Louis, Missouri 63130, USA
2 The Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, Maryland 21218, USA
Reprint requests to: Rohit V. Pappu, Department of Biomedical Engineering and Center for Computational Biology, Washington University in St. Louis, One Brookings Drive, Campus Box 1097, St. Louis, Missouri 63130, USA; e-mail: pappu{at}biomed.wustl.edu.
The striking similarity between observed circular dichroism spectra of nonprolyl homopolymers and that of regular left-handed polyproline II (PII) helices prompted Tiffany and Krimm to propose in 1968 that unordered peptides and unfolded proteins are built of PII 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 PII structure in a short unfolded alanine-based peptide. What is the physical basis for PII 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 PII 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 PII-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 PII 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.
Keywords: Configurational mapping; energy landscape; polyproline II helices; inherent structures; random-coil; packing density
Abbreviations: CD, circular dichroism • PII, left-handed polyproline II helix • NMR, nuclear magnetic resonance • NOE, nuclear Overhauser enhancement • sPII, symmetry mate of left-handed polyproline II helix • T, temperature • Ux, potential energy of conformation x • Z, configurational sum
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