Vesicle-Bound Conformation of Melittin: Transferred Nuclear Overhauser Enhancement Analysis in the Presence of Perdeuterated Phosphatidylcholine Vesicles

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Abstract

We determined a detailed conformation of the honeybee venom peptide melittin when bound to phosphatidylcholine vesicles using proton NMR. In the presence of vesicles of perdeuterated dipalmitoylglycerophosphocholine, two-dimensional transferred nuclear Overhauser enhancement (TRNOE) experiments were carried out. By a distance geometry calculation using NOE-derived distance constraints followed by a simulated annealing refinement, the N-terminal (Leu6-Leu10) and C-terminal (Leu13-Lys21) parts were found to have an alpha-helical conformation, whereas five C-terminal residues (Arg22-Gln26) did not show a unique conformation in the vesicle-bound state. The two alpha-helices were connected via a less structured segment (Thr11-Gly12) with a helix bend angle of 86 degrees +/- 34 degrees. Model distance geometry calculations using distance constraints extracted from a tetrameric melittin molecule in crystal assured us that the NOE constraints can accurately reproduce melittin's structure, as well as helping to interpret the NMR structures. Although the vesicle-bound conformation of melittin is similar to that occurring in a methanol solution and in dodecylphosphocholine micelles, significant differences were found in the conformation of C-terminal basic residues and the helix bend angle. This is the first study to clearly demonstrate conformation differences in micelle- and vesicle-bound peptides. In addition, lytic activity of melittin and its analogs showed better correlation with a peptide conformation in vesicles than in either methanol or micelles.

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