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

Danilo Roccatano*,, Giorgio Colombo**, Marco Fioroni***, and Alan E. Mark****
* Dipartimento di Chimica, Ingegneria Chimica e Materiali Universit? Degli Studi, Via Vetoio, 67010 L'Aquila, Italy;
**Istituto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Ricerche, Via Mario Bianco 9, 20131 Milan, Italy;
***Fakultat fur Chemie und Mineralogie, Institut fur Organische Chemie, Johannisallee 29, 04103 Leipzig, Germany;
**** Groningen Biomolecular Sciences and Biotechnology Institute, Department of Biophysical Chemistry, University of Groningen Nijenborgh 4, 9747 AG Groningen, The Netherlands

FULL TEXT

Abstract

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 -helix from Melittin, the three-stranded -sheet peptide Betanova, and the -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.