title: Solid-state NMR analysis comparing the designer-made antibiotic MSI-103 with its parent peptide PGLa in lipid bilayers.
abstract: The amphiphilic alpha-helical peptide (KIAGKIA)3-NH2 (MSI-103) is a designer-made antibiotic, based on the natural sequence of PGLa from Xenopus laevis. Here, we have characterized the concentration-dependent alignment and dynamic behavior of MSI-103 in lipid membranes by solid-state 2H and 19F NMR, using orientational constraints from seven Ala-d3-labeled analogues and five 4-CF3-phenylglycine labels. As previously found for PGLa, MSI-103, too, assumes a flat surface-bound S-state alignment at low peptide concentrations, and it also realigns to a tilted T-state at higher concentrations. For PGLa, the stability of the T-state had been attributed to the specific assembly of antiparallel dimers; hence, it is remarkable that the artificial KIAGKIA repeat sequence can also dimerize in the same way in liquid crystalline lipid bilayers. Oriented circular dichroism analysis shows that for MSI-103 the threshold for realignment from the S-state to the T-state is approximately 3-fold lower than for PGLa (at a peptide-to-lipid ratio of 1:240 in dimyristoylphosphatidylcholine, compared to 1:80). Furthermore, MSI-103 becomes laterally immobilized in the lipid bilayer at a concentration ratio of 1:50, which occurs for PGLa only above 1:20. The superior antimicrobial activity of MSI-103 over PGLa thus appears to correlate with its stronger tendency to realign and self-assemble. The hemolytic activities of MSI-103 and its analogues, on the other hand, are shown here to correlate purely with the respective changes in hydrophobicity.
authors.affiliation: Institute of Biological Interfaces, Forschungszentrum Karlsruhe, P.O. Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Strandberg
authors.forename: Nathalie
authors.initials: N
authors.lastname: Kanithasen
authors.forename: Deniz
authors.initials: D
authors.lastname: Tiltak
authors.forename: Jochen
authors.initials: J
authors.lastname: Bürck
authors.forename: Parvesh
authors.initials: P
authors.lastname: Wadhwani
authors.forename: Olaf
authors.initials: O
authors.lastname: Zwernemann
authors.forename: Anne S
authors.initials: AS
authors.lastname: Ulrich
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000378:metabolism; D002942:Circular Dichroism; D015198:Designer Drugs / Q000737:chemistry; D019281:Dimerization; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D009994:Osmolar Concentration; D011487:Protein Conformation; D011498:Protein Precursors / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013499:Surface Properties
chemical_list: C528508:(KIAGKIA)3 peptide; D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D015198:Designer Drugs; D008051:Lipid Bilayers; C088254:PGLa prepropeptide; D011498:Protein Precursors