Abstract
Aurein 1.2 is a 13 residue antimicrobial peptide secreted by the Australian tree frog Litoria Aurea. It is a surface-acting membrane disrupting peptide that permeabilizes bacterial membranes via the carpet mechanism; the molecular details of this process are mostly unknown. Here the mechanism of action of Aurein 1.2 was investigated with an emphasis on the role of membrane charge and C-terminal amidation of the peptide. Using quartz crystal microbalance (QCM) fingerprinting it was found that the membrane charge correlates with membrane affinity of the peptide, however the binding and the membrane disrupting processes are not charge driven; increased membrane charge reduces the membrane disrupting activity. Coarse grain simulations revealed that phenylalanine residues act as membrane anchors. Accordingly Aurein 1.2 has the ability to bind to any membrane. Furthermore, bundling precludes membrane disruption in case of wild type peptides, while non C-terminal amidated peptides form random aggregates leading to detachment from the membrane. Hence C-terminal amidation is crucial for Aurein 1.2 action. Our results suggest that Aurein 1.2 acts via aggregation driven membrane penetration. The concomitant change in the tension of the outer leaflet imposes a spontaneous curvature on the membrane, leading to disintegration.
Highlights
Entire surface of the membrane or local areas are saturated with peptide[16]
In case of the carpet action, it is assumed that at least the initial membrane binding step is electrostatically driven since antimicrobial peptides (AMPs) that follow the carpet mechanism typically carry a high positive charge[16]
Other authors suggested that C-terminal amidation can prevent the enzymatic degradation of antimicrobial peptides[35]
Summary
Entire surface of the membrane or local areas are saturated with peptide[16]. Importantly, the peptides remain tightly bound to the membrane interface throughout the mechanism[13,17,18]. The amount of binding differs by membrane type: in DMPC it is ~ − 4 Hz but the stage is only discernible at low concentrations, suggesting two competing equilibria between solution phase and surface bound peptide as well as e.g. monomeric and aggregated form on the membrane.
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