Nanoscale heterogeneity in hybrid polymer-lipid membranes creates native-like environments for integral membrane proteins

Hybrid membranes (HMs) composed of amphiphilic block copolymers and lipids exhibit nanoscale organization controlled by polymer length and weight fraction, with nanodomains forming in a narrow compositional range. Membrane-spanning objects create hydrophobic mismatch-induced defects that locally enrich lipids, forming bilayer-like structures and creating a native-like environment for integral membrane proteins. This lipid enrichment correlates with defect size and enhances specific interactions, as demonstrated by increased cardiolipin binding to synthetic proteins in HMs. These findings reveal how phase behavior and defect formation shape membrane composition and function, providing a mechanistic framework for designing synthetic membranes that combine stability with functional biomimicry.