Polymerization Chaperone for the Controlled, Homogeneous Synthesis of Proline-Based Homo- and Copolypeptides

Inspired by chaperones that prevent nascent polypeptide chains from aggregation and guide protein folding in vivo, we introduce a “polymerization chaperone” strategy to overcome the longstanding challenges in synthesizing well-defined poly-l-proline (PLP) and collagen-like copolypeptides. We demonstrate that simple acetic acid, used in stoichiometry to proline N-carboxyanhydride (Pro-NCA) monomer, acts as a multifunctional chaperone in dichloromethane. The polymerization chaperone plays triple roles: it solubilizes and stabilizes the growing polyproline type II (PPII) helix via hydrogen bonding, catalyzes the ring-opening polymerization of proline and hydroxyproline derived NCAs with high in situ selectivity of trans amide (trans ratio 0.89–0.99), and enhances chain end fidelity by improving the selective addition of carbonyl. This enables the controlled synthesis of PLP with predictable degrees of polymerization up to 400 and narrow dispersity (Đ < 1.22). Importantly, the system permits statistical copolymerization of Pro-NCA with sarcosine NCA and glycine NCA, yielding PPII helical copolypeptides that are unattainable with existing polymerization strategies. This work establishes a polymerization chaperone paradigm for in situ conformational regulation and polymerization catalysis, opening up a new avenue for the precision synthesis of insoluble homopolypeptides and collagen-like copolypeptides.