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Antimicrobial peptides (AMPs) are highly potent and broad-spectrum antibiotics, found as components of the innate immune system in almost all forms of life. Despite being commonly accepted that the mechanism of action of AMPs is associated with the permeabilization of the cell membrane, the structural and dynamical means by which this occurs are still heavily debated. In this work, we employ experimental time-resolved small angle X-ray scattering to follow in real time the AMP-induced ion transport in lipid vesicles, while simultaneously resolving the membrane structure and peptide partitioning. For several natural AMPs, we show that they can effectively permeabilize the lipid membrane despite only binding peripherally to the outer membrane leaflet. Our experiments reveal rapid ion transport associated with AMP binding, yielding salt equilibration in a few tens of milliseconds, while not detecting evidence of transversal and structurally stable peptide pores. On the contrary, new analysis of previously reported all-atom molecular dynamics simulations shows that lipid flip-flop, accelerated by the peripherally bound peptides, leads to the formation of transient, ion-conducting water channels. A corresponding diffusional model indicates that such short-lived, transient pores explain the observed ion transport better than stable pores.
Koynarev et al. (Tue,) studied this question.