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An Indirect Chaotropic Mechanism for the Stabilization of Helix Conformation of Peptides in Aqueous Trifluoroethanol and Hexafluoro-2-propanol

Richard Walgers, Tony C. Lee, and Arthur Cammers-Goodwin*

Contribution from the Department of Chemistry and the University of Kentucky Center for Membrane Sciences, University of Kentucky, Lexington, Kentucky 40506

J. Am. Chem. Soc., 1998, 120 (20), pp 5073–5079

DOI: 10.1021/ja973552z

Publication Date (Web): May 6, 1998

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

Abstract

A revised indirect mechanism is proposed for the effect of 2,2,2-trifluoroethanol on peptide conformation (TFE effect) that suggests tighter solvent shells in pure water for helical states than random coil states. The alcoholic cosolvent stabilizes the helical state preferentially by disrupting the solvent shell, which causes unfavorable enthalpic and favorable entropic contributions to the free energy of helix formation. This revised mechanism was adopted because it best explained the solvent-dependent thermodynamic behavior of the coil/helix transition. To define the TFE effect, solvent-dependent physicochemical behaviors of two molecular probes for solvent character were monitored and compared with the solvent dependence of peptide helix formation. The rate of decarboxylation of 6-nitro-3-carboxybenzisoxazole was determined in aqueous mixtures as a function of concentration for DMSO, EtOH, MeOH, ⁱPrOH, HFIP, and TFE. To relate these rate studies to the cosolvent-dependent thermodynamics of helix formation, ΔH^⧧ and ΔS^⧧ as a function of concentration for EtOH and TFE were determined and interpreted. The mixed solvent dependence of the UV spectrum of a solvatochromic ketone was also monitored to correlate the behavior of the mixed solvent systems with a microscopic polarity index.

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