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Effect of hexafluoroisopropanol alcohol on the structure of melittin: A molecular dynamics simulation study

¹ School of Engineering and Science, International University of Bremen, D-28725 Bremen, Germany
² Department of Chemistry, University of Indiana, Bloomington, Indiana 47405, USA
³ Istituto di Chimica del Riconoscimento Molecolare, CNR, 20131 Milano, Italy

(RECEIVED March 9, 2005; FINAL REVISION June 14, 2005; ACCEPTED July 6, 2005)

The molecular mechanism by which HFIP stabilizes the -helical structure of peptides is not well understood. In the present study, we use melittin as a model to gain insight into the details of the atomistic interactions of HFIP with the peptide. We have performed extensive comparative molecular dynamics simulations (up to 100 nsec) in the absence and in the presence of HFIP. In agreement with recent NMR experiments, the simulations show rapid loss of tertiary structure in water at pH 2 but much higher helicity in 35% HFIP. The MD simulations also indicate that melittin adopts a highly dynamic global structure in 35% HFIP solution with two -helical segments sampling a wide range of angular orientations. The analysis of the HFIP distribution shows the tendency of HFIP to aggregate around the peptide, increasing the local cosolvent concentration to more than two times that in the bulk concentration. The correlation of local peptide structure with HFIP coating suggests that displacement of water at the peptide surface is the main contribution of HFIP in stabilizing the secondary structure of melittin. Finally, a stabilizing effect promoted by the presence of counter-ions was also observed in the simulations.

Keywords: preferential solvation; peptide folding; -helix stability; fluorinated alcohol; cosolvent effect; helix bending

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051426605.

Reprint requests to: Danilo Roccatano, School of Engineering and Science, International University of Bremen, Campus Ring 1, D-28725 Bremen, Germany; e-mail: d.roccatano{at}iu-bremen.de; fax: +49-421-200-3249.

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