Phase Behavior of Unilamellar Hybrid Lipid-Diblock Copolymer Membranes

Abstract

Hybrid lipid block copolymer membranes are promising for many applications in drug delivery, single molecule detection, in-membrane protein folding, and synthetic cells. However, rational design is difficult due to the many design parameters which determine the nano- and micron-scale morphology and properties. In this work, we propose a physically-informed framework which incorporates chemical immiscibility, hydrophobic thickness mismatch and geometric constraints to predict the morphology of hybrid membranes. For this purpose, we extend existing theory for amphiphilic monolayers to model the thickness of diblock copolymer bilayers, demonstrating that both the hydrophobic and hydrophilic block lengths determine the thickness. We identify and rationalize the four primary membrane morphologies observed: mixed, laterally phase-separated, unzipped (thick-thin coexistence), and polymer-rich. Specifically, chemical immiscibility differentiates mixed membranes from laterally phase separated membranes, and hydrophobic mismatch drives transitions to unzipped or polymer-rich morphologies. Areal density, finally, determines the crossover between unzipped and polymer-rich states. We validate our theoretical predictions using coarse-grained molecular dynamics across a broad parameter space, including multiple lipid species (DOPC, DPPC), polymer species (1,4 PBD-b-PEO, 1,2 PBD-b-PEO, PE-b-PEO), block lengths, temperatures, and compositions. The resulting phase maps unify previously reported experimental and simulation observations and enable a generic and mechanistic understanding for the effect of system parameters on the nanoscale morphology.