Mechanism of stabilization of helical conformations of polypeptides by water containing trifluoroethanol

For conjugates Ac-Hel(1)-Ala(n)-OH, n = 1-6, of the previously characterized reporting, conformational template Ac-Hel(1), increases in helicity induced by trifluoroethanol (TFE) in water have been related to a simple function of the peptide length n, yielding the helix propagation constant s(Ala), which increases from 1.0 to 1.5 for chi(TFE) = 0-20 mol %. The per-residue helicity increase is similar to the increase in te state stability induced by TFE in monoamide conjugates Ac-Hel(1)-NHR. Addition of TEE to water significantly increases the rate of interconversion of s-cis/s-trans amide conformers for Ac-Pro-NHMe, consistent with a significant and selective destabilization of the planar resonance-stabilized amide. In dilute aqueous solution TFE increases helicity by selectively destabilizing amide functions that are solvent exposed, with the consequence that compact conformations such as helices that maximize intramolecular amide-amide hydrogen bonding and minimize amide solvent exposure are selectively favored.