THE MOLTEN HELIX - EFFECTS OF SOLVATION ON THE ALPHA-HELICAL TO 3(10)-HELICAL TRANSITION

Free energy surfaces, or potentials of mean force, for the alpha- to 3 (10)-helical conformational transition in polypeptides have been calcu lated in several solvents of different dielectric. The alpha- to 3(10) -helical transition has been suggested as potentially important in var ious biological processes, including protein folding, formation of vol tage-gated ion channels, kinetics of substrate binding in proteins, an d signal transduction mechanisms. This study investigates the thermody namics of the alpha- to 3(10)-helical transition of a model peptide, t he capped decamer of alpha-methylalanine, in order to assess the plaus ibility of this transition in the mechanisms of such biological proces ses. The free energy surfaces indicate that in each environment studie d the alpha-helical conformation is the more stable of the two for the decapeptide, The thermodynamic data suggest that the alpha-helix is e nergetically stabilized and the 3(10)-helix is entropically favored. T he inclusion of dichloromethane, acetonitrile, or water results in app roximately 7 kcal/mol of relative conformational energy (favoring the alpha-helix) and 3 kcal/mol of relative conformational entropy (favori ng the 3(10)-helix) in comparison to the gas phase. In polar environme nts, the alpha-helix is stabilized by its more favorable salute-solven t electrostatic interactions, and solute-solute steric interactions. I n 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 3(10)-helix by widening psi, the resulting weaker intrasolute h ydrogen bonds being compensated for by increased-hydrogen bonding to t he solvent. Lower polarity environments are associated with a marginal ly increased relative stability of the 3(10)-helix, which we suggest i s largely due to the additional intrahelical hydrogen bond of this con formation. The data suggest that, in environments such as membranes, t he interior of proteins or crystals, the complete transition from an c t-helix to a 3(10)-helix for this decapeptide would require less than 6 kcal/mol in free energy. Switching conformations for individual resi dues is much more facile, and shorter 3(10)-helices may actually be en ergetically favored, at least, in nonpolar environments. This study pr imarily 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 alpha- to 3(10)-helical transition could provi de a possible mechanism for many biological processes. While there are many factors, such as helix length and side chain packing, that contr ibute to the selection of either the alpha- or the 3(10)-helical confo rmation or a mixture of the two, this study focuses primarily on one o f these effects, that of the polarity of the environment.