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 <i>in vivo</i>, 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 <i>N</i>-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 <i>in situ</i> selectivity of <i>trans</i> amide (<i>trans</i> 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 (<i>Đ</i> < 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 <i>in situ</i> conformational regulation and polymerization catalysis, opening up a new avenue for the precision synthesis of insoluble homopolypeptides and collagen-like copolypeptides.