Correlation of an antimicrobial peptide's potency and its influences on membrane elasticity

Abstract

The killing power of membrane-active antimicrobial peptides (AMPs) lies in their ability to disrupt the structures of pathogenic membranes. While understanding the AMPs' mechanisms of action is key to realizing their therapeutic potentials, how the AMPs modulate membrane elasticity and thereby affect membrane structure remains an open question, even though the AMP-induced variations in membrane curvature are widely considered to be crucial. Here, we exploit the x-ray diffraction technique to examine how the dominant bacterial lipid, phosphatidylethanolamine, varies its monolayer elastic properties upon interacting with six artificial peptides mimicking the AMPs' common amino acid content. Remarkably, the monolayer spontaneous curvature ${C}_{0}$ is unaffected by any of the peptides. In contrast, the peptides designated as ${(\mathrm{K}2\mathrm{W})}^{2}$, K4W2, R6, and R9, mimicking the AMP mutants with microbicidal potency, are able to modify the monolayer bending moduli ${K}_{cp}$, while those derived from the impotent mutants cannot. The results are consistent with the scenario that the AMPs disrupt the structure of pathogenic monolayers by, additionally if not exclusively, modulating their ${K}_{cp}$'s, with stiffening and softening leading to two different modes of disruption, that is, toroidal pore formation and membrane micellation, respectively.