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Specific and Selective Peptide-Membrane Interactions Revealed Using Quartz Crystal Microbalance

Adam Mechler ^*, Slavica Praporski ^*, Kiran Atmuri ^*, Martin Boland , Frances Separovic  and Lisandra L. Martin ^*

^* School of Chemistry, Monash University, Clayton, Victoria 3800, Australia, and School of Chemistry, Bio21 Institute, University of Melbourne, Melbourne, Victoria 3010, Australia

Correspondence: Address reprint requests to Lisandra L. Martin, Tel.: 613-99054514; Fax: 613-99054514; E-mail: Lisa.Martin{at}sci.monash.edu.au.

The skin secretions of Australian tree frogs are rich in peptides with potential antimicrobial activity. They interrupt bacterial cell membranes, although precisely how and whether all peptides have the same mechanism is not known. The interactions of three of these peptides—aurein 1.2, maculatin 1.1, and caerin 1.1 with supported phospholipid bilayers—are examined here using quartz crystal microbalance and atomic force microscopy. These approaches enabled us to reveal variations in material structure and density as a function of distance from the sensor surface when comparing mass sensorgrams over a range of harmonics of the natural resonance of the sensor crystal and hence obtain for the first time to our knowledge a mechanistic assessment of membrane disruption. We found that caerin inserted into the bilayer in a transmembrane manner, regardless of concentration and phospholipid composition consistent with a pore-forming mechanism. In contrast, maculatin and aurein interacted with membranes in a concentration-dependent manner. At low concentrations (<5 µM), maculatin exhibited transmembrane incorporation whereas aurein was limited to surface association. Upon reaching a threshold value of concentration, both peptides lysed the membrane. In the case of maculatin, the lysis progressed in a slow, concentration-dependent manner, forming mixed micelles, as shown by atomic force microscopy imaging. Aurein-induced lysis proceeded to a sudden disruption, which is consistent with the "carpet" mechanism. Both maculatin and aurein exhibit specificity toward phospholipids and thus have potential as candidates as antimicrobial drugs.

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