title: Structure-activity relationships of the antimicrobial peptide gramicidin S and its analogs: aqueous solubility, self-association, conformation, antimicrobial activity and interaction with model lipid membranes.
abstract: GS10 [cyclo-(VKLdYPVKLdYP)] is a synthetic analog of the naturally occurring antimicrobial peptide gramicidin (GS) in which the two positively charged ornithine (Orn) residues are replaced by two positively charged lysine (Lys) residues and the two less polar aromatic phenylalanine (Phe) residues are replaced by the more polar tyrosine (Tyr) residues. In this study, we examine the effects of these seemingly conservative modifications to the parent GS molecule on the physical properties of the peptide, and on its interactions with lipid bilayer model and biological membranes, by a variety of biophysical techniques. We show that although GS10 retains the largely β-sheet conformation characteristic of GS, it is less structured in both water and membrane-mimetic solvents. GS10 is also more water soluble and less hydrophobic than GS, as predicted, and also exhibits a reduced tendency for self-association in aqueous solution. Surprisingly, GS10 associates more strongly with zwitterionic and anionic phospholipid bilayer model membranes than does GS, despite its greater water solubility, and the presence of anionic phospholipids and cholesterol (Chol) modestly reduces the association of both GS10 and GS to these model membranes. The strong partitioning of both peptides into lipid bilayers is driven by a large favorable entropy change opposed by a much smaller unfavorable enthalpy change. However, GS10 is also less potent than GS at inducing inverted cubic phases in phospholipid bilayer model membranes and at inhibiting the growth of the cell wall-less bacterium Acholeplasma laidlawii B. These results are discussed in terms of the comparative antibiotic and hemolytic activities of these peptides.
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Abraham
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
authors.forename: Elmar J
authors.initials: EJ
authors.lastname: Prenner
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
authors.forename: Ruthven N A H
authors.initials: RN
authors.lastname: Lewis
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045, USA.
authors.forename: Colin T
authors.initials: CT
authors.lastname: Mant
authors.affiliation: Molecular Biophysics, University of Kaiserslautern, Erwin-Schrodinger-Str. 13, 67663 Kaiserslautern, Germany.
authors.forename: Sandro
authors.initials: S
authors.lastname: Keller
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Hodges
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada. Electronic address: rmcelhan@ualberta.ca.
authors.forename: Ronald N
authors.initials: RN
authors.lastname: McElhaney
mesh_terms: D000128:Acholeplasma laidlawii / Q000187:drug effects; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D006096:Gramicidin / Q000737:chemistry* / Q000494:pharmacology*; D008051:Lipid Bilayers / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism*; D008954:Models, Biological; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D010743:Phospholipids / Q000378:metabolism; D017433:Protein Structure, Secondary; D012995:Solubility; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014867:Water / Q000737:chemistry / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D008051:Lipid Bilayers; D008563:Membrane Lipids; D010455:Peptides; D010743:Phospholipids; D014867:Water; D006096:Gramicidin; D002784:Cholesterol
keywords: Acholeplasma laidlawii B; Antimicrobial peptides; Gramicidin S (GS); Lipid model membranes; Peptide–lipid interactions; Phospholipid bilayers