Dermaseptin S9, an α-Helical Antimicrobial Peptide with a Hydrophobic Core and Cationic Termini

• Published in: Biochemistry (Easton) 2006-01, Vol.45 (2), p.468-480
• Main Authors: Lequin, Olivier, Ladram, Ali, Chabbert, Ludovic, Bruston, Francine, Convert, Odile, Vanhoye, Damien, Chassaing, Gérard, Nicolas, Pierre, Amiche, Mohamed
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - genetics; Antimicrobial Cationic Peptides - metabolism; Anura; Base Sequence; Cell Membrane Permeability - physiology; Circular Dichroism; Cloning, Molecular; Escherichia coli - metabolism; Hemolysis - physiology; Hydrophobic and Hydrophilic Interactions; Kinetics; Lipid Bilayers - chemistry; Lipid Bilayers - metabolism; Magnetic Resonance Spectroscopy; Micelles; Molecular Sequence Data; Peptide Fragments - chemistry; Peptide Fragments - genetics; Protein Binding; Protein Precursors - chemistry; Protein Precursors - genetics; Protein Structure, Secondary; Protein Structure, Tertiary; Rats; Sequence Homology, Amino Acid; Surface Plasmon Resonance; Trifluoroethanol - chemistry
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi051711i

The dermaseptins S are closely related peptides with broad-spectrum antibacterial activity that are produced by the skin of the South American hylid frog, Phyllomedusa sauvagei. These peptides are polycationic (Lys-rich), α-helical, and amphipathic, with their polar/charged and apolar amino acids on opposing faces along the long axis of the helix cylinder. The amphipathic α-helical structure is believed to enable the peptides to interact with membrane bilayers, leading to permeation and disruption of the target cell. We have identified new members of the dermaseptin S family that do not resemble any of the naturally occurring antimicrobial peptides characterized to date. One of these peptides, designated dermaseptin S9, GLRSKIWLWVLLMIWQESNKFKKM, has a tripartite structure that includes a hydrophobic core sequence encompassing residues 6−15 (mean hydrophobicity, +4.40, determined by the Liu−Deber scale) flanked at both termini by cationic and polar residues. This structure is reminiscent of that of synthetic peptides originally designed as transmembrane mimetic models and that spontaneously become inserted into membranes [Liu, L., and Deber, C. M. (1998) Biopolymers 47, 41−62]. Dermaseptin S9 is a potent antibacterial, acting on Gram-positive and Gram-negative bacteria. The structure of dermaseptin S9 in aqueous solution and in TFE/water mixtures was analyzed by circular dichroism and two-dimensional NMR spectroscopy combined with molecular dynamics calculations. Dermaseptin S9 is aggregated in water, but a monomeric nonamphipathic α-helical conformation, mostly in residues 6−21, is stabilized by the addition of TFE. These results, combined with membrane permeabilization assays and surface plasmon resonance analysis of the peptide binding to zwitterionic and anionic phospholipid bilayers, demonstrate that spatial segregation of hydrophobic and hydrophilic/charged residues on opposing faces along the long axis of a helix is not essential for the antimicrobial activity of cationic α-helical peptides.