Physical reasons for the unusual alpha-helix stabilization afforded by charged or neutral polar residues in alanine-rich peptides

We have carried out conformational energy calculations on alanine-based cop olymers with the sequence Ac-AAAAAXAAAA-NH2 in water, where X stands for ly sine or glutamine, to identify the underlying source of stability of alanin e-based polypeptides containing charged or highly soluble polar residues in the absence of charge-charge interactions. The results indicate that ioniz able or neutral polar residues introduced into the sequence to make them so luble sequester the water away from the CO and NH groups of the backbone, t hereby enabling them to form internal hydrogen bonds. This solvation effect dictates the conformational preference and, hence, modifies the conformati onal propensity of alanine residues. Even though we carried out simulations for specific amino acid sequences, our results provide an understanding of some of the basic principles that govern the process of folding of these s hort sequences independently of the kind of residues introduced to make the m soluble. In addition, we have investigated through simulations the effect of the bulk dielectric: constant on the conformational preferences of thes e peptides. Extensive conformational Monte Carte searches on terminally blo cked 10-mer and 16-mer homopolymers of alanine in the absence of salt were carried out assuming values for the dielectric constant of the solvent epsi lon of 80, 40, and 2. Our simulations show a clear tendency of these oligop eptides to augment the a-helix content as the bulk dielectric constant of t he solvent is lowered. This behavior is due mainly to a loss of exposure of the CO and NH groups to the aqueous solvent. Experimental evidence indicat es that the helical propensity of the amino acids in water shows a dramatic increase on addition of certain alcohols, such us trifluoroethanol. Our re sults provide a possible explanation of the mechanism by which alcohol/wate r mixtures affect the free energy of helical alanine oligopeptides relative to nonhelical ones.