Antimicrobial peptides (AMPs) interact directly with lipid membranes of pathogens and may have the potential to combat antibiotic resistance. Although many AMPs are thought to form toxic oligomeric pores, their interactions within lipid membranes are not well understood. Here, we used native mass spectrometry to measure the incorporation of a range of different AMPs in lipoprotein nanodiscs. We found that the truncation of human LL37 increases the lipid specificity but decreases the specificity of complex formation. We also saw that the reduction of disulfide bonds can have a dramatic effect on the ability of AMPs to interact with lipid bilayers. Finally, by examining a wider range of peptides we discovered that AMPs tend to interact specifically with anionic lipids but form nonspecific complexes with wide oligomeric state distributions. Overall, these data reveal that each AMP has unique behaviors but some common trends apply to many AMPs.
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