Mechanism by which 2,2,2-trifluoroethanol/water mixtures stabilize secondary-structure formation in peptides: A molecular dynamics study

Molecular dynamics simulation techniques have been used to investigate
the effect of 2,2,2-trifluoroethanol (TFE) as a cosolvent on the
stability of three different secondary structure-forming peptides: the
a-helix from Melittin, the three-stranded 13-sheet peptide Betanova, and
the beta-hairpin 41-56 from the B1 domain of protein G. The peptides
were studied in pure water and 30\% (vol/vol) TFE/water mixtures at 300
K. The simulations suggest that the stabilizing effect of TFE is induced
by the preferential aggregation of TFE molecules around the peptides.
This coating displaces water, thereby removing alternative
hydrogen-bonding partners and providing a low dielectric environment
that favors the formation of intrapeptide hydrogen bonds. Because TFE
interacts only weakly with nonpolar residues, hydrophobic interactions
within the peptides are not disrupted. As a consequence, TFE promotes
stability rather than inducing denaturation.