Role of molecular architecture on the relative efficacy of aurein 2.5 and modelin 5

Dennison, Sarah R., Morton, Leslie H.G. and Phoenix, David A. (2012) Role of molecular architecture on the relative efficacy of aurein 2.5 and modelin 5. Biochimica et Biophysica Acta (BBA) - Biomembranes, 1818 (9). pp. 2094-2102. ISSN 00052736

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Official URL: http://dx.doi.org/10.1016/j.bbamem.2012.05.015

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 (6.6 mN m− 1) generated greater pressure changes than modelin-5 (5.3 mN m− 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 (Kd = 75 μM) relative to modelin-5 (Kd = 118 μM) 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%).


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