Distinct Roles of the Lipid Headgroup and Acyl Chain in Peptide Adsorption to Membranes

Membrane-active peptides discriminate between target membranes largely through lipid composition, yet how specific headgroup chemistry and acyl-chain packing control peptide binding remains poorly resolved. Here, all-atom molecular dynamics simulations are used to systematically investigate the adsorption of a neutral amphipathic peptide (Ac-AKFEFKAE-NH2) onto 14 bilayers composed of either phosphatidylcholine (PC) or phosphatidylethanolamine (PE) lipids mixed 7:3 with phosphatidylglycerol (PG), where the acyl-chain length and saturation are varied independently. We find that adsorption is enhanced in PE relative to PC membranes and in bilayers with shorter or unsaturated acyl chains. Electrostatic interactions drive the initial attraction of peptides to the membrane and promote local enrichment of anionic PG lipids around the peptide. Also, the N+H3 terminal group of PE headgroups is found to interact favorably with anionic residues, an interaction sterically hindered in PC lipids by their bulkier N+(CH3)3 terminal. We find that lipids also affect the kinetics of adsorption: peptides insert more rapidly onto PE membranes than onto PC membranes, while lipid unsaturation extends the peptide’s residence time at the bilayer. We also find that upon adsorbing, peptides become localized within the PE headgroup region. In PC membranes, nonpolar residues localize deeper below the lipid headgroup region. Together, these results show that headgroup chemistry and acyl-chain packing jointly govern the extent and rate of peptide binding, while lipid unsaturation additionally tunes membrane residence time─defining a compositional code underlying how membrane-active peptides selectively recognize lipid bilayers.