title: Role of molecular architecture on the relative efficacy of aurein 2.5 and modelin 5.
abstract: In order to gain an insight into the mechanism of antimicrobial peptide action, aurein 2.5 and modelin-5 were studied. When tested against Staphylococcus aureus, aurein 2.5 showed approximately 5-fold greater efficacy even though the higher net positive charge and higher helix stability shown by modelin-5 would have predicated modelin-5 to be the more effective antimicrobial. However, in the presence of S. aureus membrane mimics, aurein 2.5 showed greater helical content (75% helical) relative to modelin-5 (51% helical) indicative of increase in membrane association. This was supported by monolayer data showing that aurein 2.5 (6.6mNm(-1)) generated greater pressure changes than modelin-5 (5.3mNm(-1)). Peptide monolayers indicted that modelin-5 formed a helix horizontal to the plane of an asymmetric interface which would be supported by the even distribution of charge and hydrophobicity along the helical long axis and facilitate lysis by non-specific membrane binding. In contrast, a groove structure observed on the surface of aurein 2.5 was predicted to be the cause of enhanced lipid binding (K(d)=75μM) relative to modelin-5 (K(d)=118μM) and the balance of hydrophobicity along the aurein 2.5 long axis supported deep penetration into the membrane in a tilt formation. This oblique orientation generates greater lytic efficacy in high anionic lipid (71%) compared to modelin-5 (32%).
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, UK.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Dennison
authors.forename: Leslie H G
authors.initials: LH
authors.lastname: Morton
authors.forename: David A
authors.initials: DA
authors.lastname: Phoenix
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000737:chemistry*; D001703:Biophysics / Q000379:methods; D002462:Cell Membrane / Q000378:metabolism; D002942:Circular Dichroism; D004926:Escherichia coli / Q000378:metabolism; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry*; D008055:Lipids / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D010715:Phosphatidylglycerols / Q000032:analysis; D010743:Phospholipids / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013211:Staphylococcus aureus / Q000378:metabolism*; D013499:Surface Properties; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D023181:Antimicrobial Cationic Peptides; D008051:Lipid Bilayers; D008055:Lipids; D010455:Peptides; D010715:Phosphatidylglycerols; D010743:Phospholipids; C535241:aurein 2.5 peptide, Litoria aurea; C089690:modelin 5