A model for the interaction of trifluoroethanol with peptides and proteins.

The structural stabilizing property of 2,2,2-trifluoroethanol (TFE) in peptides has been widely demonstrated. More recently, TFE has been shown to enhance secondary structure content in globular proteins, and to influence quaternary interactions in protein multimers. The molecular mechanisms by which TFE exerts its influence on peptide and protein structures remain poorly understood. The present analysis integrates the known physical properties of TFE with a variety of experimental observations on the interaction of TFE with peptides and proteins and on the properties of fluorocarbons. Two features of TFE, namely the hydrophobicity of the trifluoromethyl group and the hydrogen bonding character (strong donor and poor acceptor), emerge as the most important factors for rationalising the observed effects of TFE. A model is proposed for TFE interaction with peptides which involves an initial replacement of the hydration shell by fluoroalcohol molecules, a process driven by apolar interactions and favourable entropy of dehydration. Subsequent bifurcated hydrogen-bond formation with peptide carbonyl groups, which leave intramolecular interactions unaffected, promotes secondary structure formations.