Seeding Crystals, Harvesting Polypeptides: Preparing Long Chiral-Sequence Controlled Polypeptides by Interlocked Polymerization in Cocrystals (iPiC) of N‑Thiocarboxyanhydride (NTA) at Room Temperature

Nature creates sophisticated proteins via programming amino acid monomers. In contrast, the chemical approach toward both long and sequence-controlled polypeptides still remains a challenge. Inspired by Nature, we develop a novel topochemical reaction named “interlocked polymerization in cocrystals” (iPiC) toward long chiral-sequence controlled polypeptides with a DL-alternating order. By crystallization, racemic methionine N-thiocarboxyanhydride (rac-Met-NTA) is programmed as D/L pairs located in the “sandwich” structure separated by the thioether side group layer and polymerized pair-by-pair in the lattice. iPiC of rac-Met-NTA produces P­(d/l-Met) up to a polymer degree (DP) of 148 at room temperature (25 °C) with dispersity (D̵) in 3–7 days. A chiral D/L sequence is produced via iPiC from rac-Met-NTA in an achiral environment. Solution polymerization of racemic and l-rich Met-NTA cases is investigated to illustrate the role of the secondary structure in iPiC. Zeroth-order kinetics is confirmed, and in situ microscopic tracing is exhibited. According to theoretical calculations and Monte Carlo simulations, D̵ of polypeptides is an increasing function of the relative standard deviation (σ/μ) of the cocrystal size d when d follows normal distribution, which is also confirmed by experimental results. In determining σ/μ of the cocrystals from microscopic images, a novel digital imaging process is introduced to accelerate the counting process. Based on the monomer programming strategy, iPiC paves the way toward long chiral-sequence controlled polypeptides using simple initiators in an achiral system.