title: Solution structure of a novel tryptophan-rich peptide with bidirectional antimicrobial activity.
abstract: Trp-rich antimicrobial peptides play important roles in the host innate defense mechanisms of many plants, insects, and mammals. A new type of Trp-rich peptide, Ac-KWRRWVRWI-NH(2), designated Pac-525, was found to possess improved activity against both gram-positive and -negative bacteria. We have determined that the solution structures of Pac-525 bound to membrane-mimetic sodium dodecyl sulfate (SDS) micelles. The SDS micelle-bound structure of Pac-525 adopts an alpha-helical segment at residues Trp2, Arg3, and Arg4. The positively charged residues are clustered together to form a hydrophilic patch. The three hydrophobic residues Trp2, Val6, and Ile9 form a hydrophobic core. The surface electrostatic potential map indicates the three tryptophan indole rings are packed against the peptide backbone and form an amphipathic structure. Moreover, the reverse sequence of Pac-525, Ac-IWRVWRRWK-NH(2), designated Pac-525(rev), also demonstrates similar antimicrobial activity and structure in membrane-mimetic micelles and vesicles. A variety of biophysical and biochemical methods, including circular dichroism, fluorescence spectroscopy, and microcalorimetry, were used to show that Pac-525 interacted strongly with negatively charged phospholipid vesicles and induced efficient dye release from these vesicles, suggesting that the antimicrobial activity of Pac-525 may be due to interactions with bacterial membranes.
authors.affiliation: Pacgen Biopharmaceuticals Corp., 1730-505 Burrard Street, Vancouver, BC V7X 1M6, Canada.
authors.forename: Shu-Yi
authors.initials: SY
authors.lastname: Wei
authors.forename: Jiun-Ming
authors.initials: JM
authors.lastname: Wu
authors.forename: Yen-Ya
authors.initials: YY
authors.lastname: Kuo
authors.forename: Heng-Li
authors.initials: HL
authors.lastname: Chen
authors.forename: Bak-Sau
authors.initials: BS
authors.lastname: Yip
authors.forename: Shiou-Ru
authors.initials: SR
authors.lastname: Tzeng
authors.forename: Jya-Wei
authors.initials: JW
authors.lastname: Cheng
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000494:pharmacology*; D002151:Calorimetry; D002463:Cell Membrane Permeability / Q000187:drug effects; D002942:Circular Dichroism; D004912:Erythrocytes; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D013050:Spectrometry, Fluorescence; D014364:Tryptophan / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D009842:Oligopeptides; D014364:Tryptophan