The Molten Helix: Effects of Solvation on the α- to 310-Helical Transition

Mark L. Smythe, Shawn E. Huston, Garland R. Marshall

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Abstract

Free energy surfaces, or potentials of mean force, for the α- to 310-helical conformational transition in polypeptides have been calculated in several solvents of different dielectric. The α- to 310-helical transition has been suggested as potentially important in various biological processes, including protein folding, formation of voltage-gated ion channels, kinetics of substrate binding in proteins, and signal transduction mechanisms. This study investigates the thermodynamics of the α- to 310-helical transition of a model peptide, the capped decamer of α-methylalanine, in order to assess the plausibility of this transition in the mechanisms of such biological processes. The free energy surfaces indicate that in each environment studied the α-helical conformation is the more stable of the two for the decapeptide. The thermodynamic data suggest that the α-helix is energetically stabilized and the 310-helix is entropically favored. The inclusion of dichloromethane, acetonitrile, or water results in approximately 7 kcal/mol of relative conformational energy (favoring the α-helix) and 3 kcal/mol of relative conformational entropy (favoring the 310-helix) in comparison to the gas phase. In polar environments, the α-helix is stabilized by its more favorable solute—solvent electrostatic interactions, and solute—solute steric interactions. In addition, it was concluded that in polar solvents, especially water, it is possible for the peptide to reduce some of the inherent strain of the 310-helix by widening ψ, the resulting weaker intrasolute hydrogen bonds being compensated for by increased hydrogen bonding to the solvent. Lower polarity environments are associated with a marginally increased relative stability of the 310-helix, which we suggest is largely due to the additional intrahelical hydrogen bond of this conformation. The data suggest that, in environments such as membranes, the interior of proteins or crystals, the complete transition from an α-helix to a 310-helix for this decapeptide would require less than 6 kcal/mol in free energy. Switching conformations for individual residues is much more facile, and shorter 310-helices may actually be energetically favored, at least, in nonpolar environments. This study primarily estimates the backbone contribution to the helical transition; side chain interactions would be expected to play a significant role in stabilizing one conformer relative to the other. It is, therefore, quite feasible that the α- to 310-helical transition could provide a possible mechanism for many biological processes. While there are many factors, such as helix length and side chain packing, that contribute to the selection of either the α- or the 310-helical conformation or a mixture of the two, this study focuses primarily on one of these effects, that of the polarity of the environment.

Original languageEnglish
Pages (from-to)5445-5452
Number of pages8
JournalJournal of the American Chemical Society
Volume117
Issue number20
DOIs
StatePublished - May 1995

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