Eric J. Sorin, Young Min Rhee, Michael R. Shirts, and Vijay S. Pande. Journal of Molecular Biology (2006)
SUMMARY: How complicated is a helix, and how is the complexity of helical structure affected by the solvent? Here we show, through a novel “computational hydrophobic titration” experiment, that many features of helices can be rationalized and/or explained by considering the interactions along the peptide-solvent interface.
TECHNICAL ABSTRACT: The 21-residue polyalanine-based Fs peptide was studied using thousands of long, explicit solvent, atomistic molecular dynamics simulations which reached equilibrium at the ensemble level. Peptide conformational preference as a function of hydrophobicity was examined using a spectrum of explicit solvent models, and the peptide length dependence of the hydrophilic and hydrophobic components of solvent-accessible surface area for several ideal conformational types was also considered. Our results demonstrate how the character of the solvation interface induces several conformational preferences, including a decrease in mean helical content with increased hydrophilicity, which occurs predominantly through reduced nucleation tendency and, to a lesser extent, destabilization of helical propagation. Interestingly, an opposing effect occurs through increased propensity for 310-helix conformations, as well as increased polyproline structure. Our observations provide a framework for understanding previous reports of conformational preferences in polyalanine-based peptides including (i) terminal 310-helix prominence, (ii) low p-helix propensity, (iii) increased polyproline conformations in short and unfolded peptides, and (iv) membrane helix stability in the presence and absence of water. These observations lend physical insight into the role of water in peptide conformational equilibria at the atomic level, and expand our view of the complexity of even the most “simple” of biopolymers. Whereas previous studies have focused predominantly on hydrophobic effects with respect to tertiary structure, this report highlights the need for consideration of such effects on the secondary structural level.