Trifluoroethanol may form a solvent matrix for assisted hydrophobic interactions between peptide side chains

Several models for interactions between trifluoroethanol (TFE)and peptides and proteins have recently been proposed, but nonehave been able to rationalize the puzzling observations thaton the one hand TFE can stabilize some hydrophobic interactionsin secondary structures, but on the other can also melt thehydrophobic cores of globular proteins. The former is illustratedin this paper by the effect of TFE on a short elastin peptide,GVG(VPGVG)₃, which forms type II ß-turns stabilized byhydrophobic interactions between two intra-turn valine sidechains. This folding, driven by increasing the entropy of bulkwater, is stimulated in TFE–water mixtures and/or by raisingthe temperature. To explain these apparently contradictory observations,we propose a model in which TFE clusters locally assist thefolding of secondary structures by first breaking down interfacialwater molecules on the peptide and then providing a solventmatrix for further side chain–side chain interactions.This model also provides an explanation for TFE-induced transitionsbetween secondary structures, in which the TFE clusters mayredirect non-local to local interactions.