“Teflon-coated peptides”: Hexafluoroacetone trihydrate as a structure stabilizer for peptides

In the last 30 years, since the early work of Goodman and co-workers introducing trifluoroethanol as a solvent in peptide conformational analysis,1,2 the ability of fluoroalcohols to stabilize secondary structures in peptides in aqueous solution is well documented.3–7 However, the detailed molecular mechanisms remain to be understood. 3,4,8–12 2,2,2-Trifluoroethanol (TFE) has been the most widely used fluoroalcohol additive to aqueous solutions of peptides and proteins.4,13–18 We describe in this communication the superior structure-stabilization properties of hexafluoroacetone trihydrate (HFA, a covalent hydrate, of the ketone, a gem diol, hexafluoropropan-2,2- diol) 19–21 and provide a rationale for the induction of intramolecularly hydrogen-bonded conformations in peptides, in aqueous fluoroalcohol solutions.