FREE-ENERGY DETERMINANTS OF ALPHA-HELIX INSERTION INTO LIPID BILAYERS

A detailed treatment is provided of the various free-energy terms that contribute to the transfer of a polyalanine ct-helix from the aqueous phase into lipid bilayers. In agreement with previous work, the hydro phobic effect is found to provide the major driving force for helix in sertion, However, an opposing effect of comparable magnitude is also i dentified and is attributed to the large free-energy penalty associate d with the desolvation of peptide hydrogen bonds on transfer to the lo w dielectric environment of the bilayer. Lipid perturbation effects as well as the entropy loss associated with helix immobilization in the bilayer are also evaluated. Two configurations of a membrane-bound 25m er polyalanine helix were found to be lower in free energy than the is olated helix in the aqueous phase, The first corresponds to the case o f vertical insertion, in which a helix terminus protrudes from each si de of the bilayer. The second minimum is for the case of horizontal in sertion, for which the helix is adsorbed upon the surface of the bilay er. The calculated free-energy minima are found to be in good agreemen t with recent measurements of related systems, Large free-energy barri ers resulting from desolvation of unsatisfied hydrogen-bonding groups al the helix termini are obtained for both insertion processes. The ba rriers for insertion are significantly reduced if the helix termini ar e assumed to be ''capped'' through the formation of hydrogen bonds wit h polar sidechains, For uncapped helices, our results support recently proposed models in which helices are inserted by first adsorbing on t he membrane surface and then having one terminus ''swing around'' so a s to penetrate the bilayer,