A high-throughput platform for efficient exploration of functional polypeptide chemical space

Rapid and in-depth exploration of the chemical space of high-molecular-weight synthetic polypeptides via ring-opening polymerization of N -carboxyanhydride allows the discovery of protein mimics and functional biomaterials. The traditional synthetic workflow, however, is labour intensive and has limited throughput. Here we develop an approach for the high-throughput diversification of polypeptides based on a click-like reaction between selenolate and various electrophiles in aqueous solutions. Importantly, the platform is amenable to automation, which allows rapid generation of up to 1,200 homopolypeptides or random heteropolypeptides (RHPs) within one day. With the assistance of machine learning, iterative exploration of the RHP library identifies candidates with improved glutathione peroxidase-like activity from the complex chemical space of which we have little previous knowledge. This automated and high-throughput platform provides potential solutions to unmet challenges, such as the de novo design of artificial enzymes, biomacromolecule delivery and understanding of intrinsically disordered proteins.