Membrane Proteins at Scale: Automated Copolymer Nanodisc Purification for Structure and Function

Membrane proteins remain among the most important yet least accessible classes of drug targets. Conventional detergents can remove native lipids, destabilizing proteins and limiting downstream biochemistry and structural biology. Amphiphilic copolymers offer a powerful alternative, directly extracting membrane proteins in their native lipid environment, but solubilization outcomes remain unpredictable, turning each new target into a slow empirical search. Here, we introduce an automated, plate-based copolymer screening platform that compresses this process from days to hours using millilitre-scale volumes. Lyophilized copolymer libraries combined with magnetic-bead affinity purification enable parallel testing of dozens of copolymers against multiple targets; across 14 diverse human membrane proteins, next-generation copolymers (AASTY, CyclAPol and Cubipol) systematically outperform classical scaffolds. In this work, we show that this automated copolymer screening robustly identifies the right target-copolymer combination, yielding native-like, active, ligand-binding competent protein suitable for structure determination, and establishes a scalable route to systematic exploration of the membrane proteome.