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Conformational Changes in Alamethicin Associated with Substitution of Its -Methylalanines with Leucines: A FTIR Spectroscopic Analysis and Correlation with Channel Kinetics

Parvez I. Haris ^*, Gérard Molle  and Hervé Duclohier 

^* School of Molecular Sciences, De Montfort University, Leicester LE1 9BH, United Kingdom; Unite Mixte de Recherche 5048 Centre National de la Recherche Scientifique-Universite de Montpellier 1, 34090 Montpellier, France; and Unite Mixte de Recherche 6026 Centre National de la Recherche Scientifique-Universite de Rennes I, Campus de Beaulieu, 35042 Rennes, France

Correspondence: Address reprint requests to Dr. Herve Duclohier, E-mail: herve.duclohier{at}univ-rennes1.fr.

Alamethicin, a 20 residue-long peptaibol remains a favorite high voltage-dependent channel-forming peptide. However, the structural significance of its abundant noncoded residues (-methylalanine or Aib) for its ion channel activity remains unknown, although a previous study showed that replacement of all Aib residues with leucines preserved the essential channel behavior except for much faster single-channel events. To correlate these functional properties with structural data, here we compare the secondary structures of an alamethicin derivative where all the eight Aibs were replaced by leucines and the native alamethicin. Fourier transform infrared (FTIR) spectra of these peptides were recorded in methanol and in aqueous phospholipid membranes. Results obtained show a significant conformational change in alamethicin upon substitution of its Aib residues with Leu. The amide I band occurs at a lower frequency for the Leu-derivative indicating that its -helices are involved in stronger hydrogen-bonding. In addition, the structure of the Leu-derivative is quite sensitive to membrane fluidity changes. The amide I band shifts to higher frequencies when the lipids are in the fluid phase. This indicates either a decreased solvation due to a more complete peptide insertion or a peptide stretching to match the full thickness of the bilayer. These results contribute to explain the fast single-channel kinetics displayed by the Leu-derivative.