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We describe the challenging solid-phase synthesis of the medium-length (14 amino-acid residues) peptaibiotic ampullosporin A, originally extracted from the fungus Sepedonium ampullosporum, and an analog doubly spin labeled (at positions 3 and 13) with the stable nitroxyl free-radical 4-amino-1-oxyl-2,2,6,6-tetramethylpiperidine-4-carboxylic acid (TOAC). The results of a circular dichrosim investigation in methanol strongly support the view that both peptides are essentially right-handed helical, in particular endowed with a large population of α-helical conformers. We also observed a significant quenching effect from the TOAC3 nitroxyl radical on the fluorescence of Trp1, compatible with that expected when both residues are closely located on the same helix segment. Combined continuous wave and pulsed electron-electron double resonance electron paramagnetic resonance methodologies converge on the conclusion obtained from the other aforementioned spectroscopies, namely, that the [TOAC3,13] ampullosporin A analog is mostly folded in the α-helical conformation. A liposome leakage assay demonstrated that the membrane-modifying properties of this bis-labeled analog are remarkable and even slightly superior to those of the natural peptaibiotic itself. © 2013 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 40–48, 2014. |
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