Field coupling as an interpretative framework for peptide–membrane interactions

Abstract Antimicrobial peptides (AMPs) interact with lipid membranes through multistep processes that may include interfacial adsorption, partial insertion, membrane deformation, pore formation, and transmembrane organization. Although these processes have been extensively investigated, a unified operational framework connecting surface-bound, inserted, and intermediate peptide–membrane states remains underdeveloped. Here, we present a regime-based field-coupling framework that organizes peptide–membrane interactions according to the relative predominance of interfacial electrostatic coupling, hydrophobic-core coupling, and mixed coupling contributions. Surface-bound states are characterized primarily by interactions between cationic peptide residues and anionic lipid headgroups, whereas inserted states display stronger engagement of nonpolar peptide surfaces with lipid acyl chains. Mixed and pore-associated states retain both polar and hydrophobic interactions and may additionally involve water penetration, lipid-headgroup reorientation, membrane thinning, curvature, and peptide oligomerization. The operational use of the framework integrates peptide charge and charge distribution, hydrophobic moment, length and topology, membrane anionic charge, acyl-chain saturation, bilayer thickness, and peptide concentration. These variables are related to coordinated computational and experimental observables, including insertion depth, peptide–headgroup contacts, nonpolar residue–acyl-chain contacts, anionic lipid enrichment, peptide orientation, membrane order, water penetration, deformation, and peptide–peptide association. The framework generates conditional and falsifiable predictions for surface-bound, inserted/core, carpet-like, barrel-stave, and mixed/toroidal regimes. Its application to representative peptide–membrane systems illustrates how published observations can be organized within a common operational map. The proposed framework remains qualitative, and quantitative boundaries between coupling regimes require validation across peptides and membranes with distinct physicochemical properties. Nevertheless, it provides a structured basis for comparing mechanisms, designing computational and experimental tests, and interpreting transitions among peptide–membrane interaction states.