title: Interaction of gramicidin S and its aromatic amino-acid analog with phospholipid membranes.
abstract: To investigate the mechanism of interaction of gramicidin S-like antimicrobial peptides with biological membranes, a series of five decameric cyclic cationic beta-sheet-beta-turn peptides with all possible combinations of aromatic D-amino acids, Cyclo(Val-Lys-Leu-D-Ar1-Pro-Val-Lys-Leu-D-Ar2-Pro) (Ar identical with Phe, Tyr, Trp), were synthesized. Conformations of these cyclic peptides were comparable in aqueous solutions and lipid vesicles. Isothermal titration calorimetry measurements revealed entropy-driven binding of cyclic peptides to POPC and POPE/POPG lipid vesicles. Binding of peptides to both vesicle systems was endothermic-exceptions were peptides containing the Trp-Trp and Tyr-Trp pairs with exothermic binding to POPC vesicles. Application of one- and two-site binding (partitioning) models to binding isotherms of exothermic and endothermic binding processes, respectively, resulted in determination of peptide-lipid membrane binding constants (K(b)). The K(b1) and K(b2) values for endothermic two-step binding processes corresponded to high and low binding affinities (K(b1) >or= 100 K(b2)). Conformational change of cyclic peptides in transferring from buffer to lipid bilayer surfaces was estimated using fluorescence resonance energy transfer between the Tyr-Trp pair in one of the peptide constructs. The cyclic peptide conformation expands upon adsorption on lipid bilayer surface and interacts more deeply with the outer monolayer causing bilayer deformation, which may lead to formation of nonspecific transient peptide-lipid porelike zones causing membrane lysis.
authors.affiliation: Department of Chemistry, Wilfrid Laurier University, Waterloo, Ontario, Canada. mjelokhani@wlu.ca
authors.forename: Masoud
authors.initials: M
authors.lastname: Jelokhani-Niaraki
authors.forename: Robert S
authors.initials: RS
authors.lastname: Hodges
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Meissner
authors.forename: Una E
authors.initials: UE
authors.lastname: Hassenstein
authors.forename: Laura
authors.initials: L
authors.lastname: Wheaton
mesh_terms: D000595:Amino Acid Sequence; D024322:Amino Acids, Aromatic / Q000737:chemistry*; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002151:Calorimetry; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism*; D002942:Circular Dichroism; D031541:Fluorescence Resonance Energy Transfer; D006096:Gramicidin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006461:Hemolysis / Q000187:drug effects; D010743:Phospholipids / Q000378:metabolism*; D017433:Protein Structure, Secondary
chemical_list: D024322:Amino Acids, Aromatic; D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D010743:Phospholipids; D006096:Gramicidin