Sequence Patterning Governs Lipid-Selective Insertion and Membrane Perturbation of Antimicrobial Peptoids

Understanding how molecular sequence encodes membrane activity is central to the development of membrane-active agents. Peptoids, or poly-N-substituted glycines, are promising membrane-active peptidomimetics because of their stability, protease resistance, and tunable amphiphilicity. Yet, the molecular determinants governing their lipid-selective membrane interactions remain incompletely understood. Here, we employ extensive all-atom molecular dynamics simulations to investigate how alternating and diblock antimicrobial peptoid sequences interact with model bacterial membranes of varying lipid compositions. Insertion depth, residue-lipid contacts, and bilayer structural responses were quantified to characterize sequence- and composition-dependent behavior. Insertion depends strongly on the lipid composition and amphiphilic organization. The increased anionic content promotes deeper insertion, while alternating sequences distribute hydrophobic contacts more uniformly and diblock architectures induce localized membrane perturbations. Correlation analysis and principal component analysis reveal that residue-lipid contact density is most strongly associated with insertion depth, whereas global compactness contributes minimally. Deeper insertion is accompanied by localized reduction in membrane thickness, reflecting the bilayer structural response to contact-driven penetration. These findings identify molecular associations among sequence patterning, lipid composition, and local membrane structural response in antimicrobial peptoids, clarifying the molecular basis of lipid-selective insertion in sequence-defined peptidomimetics.