Glycine N‑Thiocarboxyanhydride: A Key to Glycine-Rich Protein Mimics

Glycine-rich proteins (GRPs) containing a high content of glycine residues (>30%) possess unique structural stability. However, the controllable synthesis of glycine-rich poly(amino acid)s (PAAs) to mimic GRPs has not been realized yet due to the poor solubility of polyglycine segments. We developed a novel method to synthesize glycine-rich PAAs via the controlled ring-opening copolymerization of glycine-N-thiocarboxyanhydrides (Gly-NTA) with sarcosine-N-carboxyanhydride and ε-Cbz-l-lysine-N-carboxyanhydride. The random copolymerization is evidenced by a kinetic study that shows that the propagation rate constant of Gly-NTA is close to those of comonomers. The copolymers exhibit predictable molecular weights between 4.5 and 24.6 kg/mol and tunable glycine incorporation, varying from 10.3 to 59.2%. Poly(Gly-r-Sar) samples with various glycine contents form nanoparticles or a hydrogel in water. Remarkably, the β-sheet folding of poly(Gly-r-Lys) remains intact in a neutral environment where the amine groups are protonated. Overall, the strategy paves the way to engineer glycine-rich PAAs and thereby expands their applications.