Lipid tails modulate antimicrobial peptide membrane incorporation and activity

• Published in: Biochimica et biophysica acta. Biomembranes 2022-04, Vol.1864 (4), p.183870-183870, Article 183870
• Main Authors: Walker, Lawrence R., Marty, Michael T.
• Format: Article
• Language: English
• Subjects: Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - metabolism; Antimicrobial peptides; Antimicrobial Peptides - chemistry; Antimicrobial Peptides - metabolism; Cathelicidins; Lipid Bilayers - chemistry; Lipid Bilayers - metabolism; LL-37; Magainins - chemistry; Magainins - metabolism; Mass Spectrometry; Membrane interactions; Nanodiscs; Nanostructures - chemistry; Native mass spectrometry
• ISSN: 0005-2736; 1879-2642
• DOI: 10.1016/j.bbamem.2022.183870

Membrane disrupting antimicrobial peptides (AMPs) are often amphipathic peptides that interact directly with lipid bilayers. AMPs are generally thought to interact mostly with lipid head groups, but it is less clear how the lipid alkyl chain length and saturation modulate 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 unilamellar vesicle leakage assays. We found that LL-37 formed specific hexamer complexes but with different intermediates 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 bilayers with thinner, less fluid lipids. Finally, magainin-2 incorporated to a higher degree into bilayers with longer, unsaturated alkyl chains 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. [Display omitted] •Native MS probed AMP incorporation into nanodiscs with different lipid tails.•LL-37 prefers lipids with longer alkyl chains and forms hexamer complexes.•Indolicidin activity is not correlated with membrane incorporation.•Magainin-2 has higher activity and incorporation in thicker and more fluid lipids.•Lipid tails can affect AMP incorporation, complex formation, and activity.