Lipid Tails Modulate Antimicrobial Peptide Membrane Incorporation and Activity

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Abstract
Antimicrobial peptides (AMPs) are cationic, amphipathic peptides that interact directly with lipid bilayers. AMPs generally interact with anionic lipid head groups, but it is less clear how the lipid tail length and saturation modulates interactions with membranes. Here we used native mass spectrometry to measure the stoichiometry of three different AMPs—LL-37, indolicidin, and magainin-2—in lipid nanodiscs. We also measured the activity of these AMPs in large unilamellar vesicle leakage assays. We found that LL-37 formed specific hexamer complexes but with different assembly pathways and affinities that depended on the bilayer thickness. LL-37 was also most active in lipid bilayers containing longer, unsaturated lipids. In contrast, indolicidin incorporated to a higher degree into more fluid lipid bilayers but was more active with thinner, less fluid bilayers. Finally, magainin-2 incorporated to a higher degree into longer, unsaturated bilayers and showed more activity in these same conditions. Together, these data show that higher amounts of peptide incorporation generally led to higher activity and that AMPs tend to incorporate more into longer unsaturated lipid bilayers. However, the activity of AMPs was not always directly related to amount of peptide incorporated. Graphical

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