Biophysical determinants of membranotropism: how proteins and peptides recognize, insert into, and remodel lipid bilayers

Abstract Biological membranes are not passive barriers, but chemically heterogeneous and physically adaptable interfaces that regulate how proteins and peptides bind, fold, assemble, and act. Many membrane-active systems cannot be adequately described as simply soluble, peripheral, or transmembrane. Instead, they populate multiple membrane-associated states, ranging from transient surface adsorption to interfacial partitioning, insertion, oligomerization, pore formation, fusion, and large-scale membrane remodeling. In this review, we discuss membranotropism as a unifying concept to describe the propensity of proteins, peptides, and supramolecular assemblies to associate with lipid bilayers and modify their structure, organization, or function. We bring together biophysical principles that connect membrane composition, lipid packing, curvature, sterol availability, lateral heterogeneity, oxidative state, molecular crowding, and membrane mechanics with molecular features such as amphipathicity, charge distribution, conformational plasticity, lipid-recognition motifs, and cooperative assembly. This conceptual perspective is illustrated with examples that include antimicrobial and antifungal peptides, viral fusion peptides, pore-forming toxins, peripheral and amphitropic proteins, monotopic enzymes, septin scaffolds, secreted membrane modulators, and condensate–membrane systems. We also highlight how complementary experimental and computational approaches can resolve membrane binding, partitioning, insertion, remodeling, and functional membrane activity across different length and time scales. By integrating molecular architecture with membrane biophysics, membranotropism provides a useful perspective for understanding how membrane recognition is converted into biological activity. We also discuss how this concept can guide the development of antimicrobial, antiviral, antiparasitic, anticancer, and delivery-oriented strategies based on the selective targeting or remodeling of lipid membranes.