Adsorption of Amphipathic Peptides on Lipid Membranes: Effects of Lipid Headgroup Size and Acyl Tail Length

Peptide-membrane interactions are critical in biological processes like antimicrobial activity, drug delivery, and amyloid aggregation. Their selective binding depends not only on peptide sequence but also on target membrane composition. Using all-atom molecular dynamics simulations, we systematically investigate the influence of lipid headgroup chemistry and acyl tail properties on the adsorption of amphipathic model peptide Ac-AKFEFKAE-NH₂. Fourteen model membranes composed of PC:PG or PE:PG mixtures with varied tail lengths and saturation states were studied. Our results show that membranes containing phosphatidylethanolamine (PE) headgroups consistently exhibit higher peptide adsorption with stronger binding than those with phosphatidylcholine (PC), primarily due to enhanced electrostatic interactions and increased PG accessibility. Unsaturated acyl tails, despite their longer length, facilitate stronger peptide binding than saturated ones, indicating that tail disorder outweighs tail length effects. Peptide binding induces membrane expansion and tail disorder, but headgroup orientation remains intact. These findings underscore the critical role of lipid headgroup identity and tail saturation in governing peptide-membrane interactions.