Proximity-Induced Cooperative Polymerization in “Hinged” Helical Polypeptides

Abstract

Cooperative interactions and transitions are among the most important strategies utilized by biological systems to regulate a variety of physical and chemical processes. We report herein an auto-accelerated, rapid cooperative polymerization of N-carboxyanhydrides (NCAs) with initiators structurally as simple as linear aliphatic diamines for the synthesis of polypeptides. The polymerization initiated by diamines proceeds via the formation of "hinged" polypeptides, which are two blocks of helical chains connected head-to-head by the diamine molecules in the polymerization solution. The reactions follow a two-stage, cooperative polymerization kinetic; the cooperative interactions between the macrodipoles of the two hinged helical polypeptides dramatically accelerate the polymerization. Compared to the NCA polymerization initiated by the hexylamine (CH 3 (CH 2 ) 5 NH 2 ), the chain propagation rate of the NCA polymerization is increased by more than 600 times when initiated by its diamine analogue (1,6-diaminohexane, NH 2 (CH 2 ) 6 NH 2 ). This proximity-induced cooperative polymerization showcases the single helix as a remarkable cooperativityenabling motif in synthetic chemistry.

Aqueous Ring‐Opening Polymerization‐Induced Self‐Assembly (ROPISA) of N‐Carboxyanhydrides

“…Under these experimental conditions ([M] 0 =0.14 m ), the apparent kinetic rate for ROPISA initiated by an α‐amino‐poly(ethylene glycol) is 0.14 m −1 s −1 , as calculated from FTIR analyses (see Figure SI 11). This kinetic rate is in the range of previously measured ROP of BLG‐NCA enhanced by proximity‐induced cooperative polymerization . To further study the kinetics of this aqueous ROP process, we followed the polymerization propagation using a quenching method (see Mat&Meth SI).…”

“…Overall, the ROPISA of BLG‐NCA initiated by PEG 5K is a facile and robust process to prepare well‐defined amphiphilic polypeptide in aqueous solution and to access their related nanomaterials at unprecedented solids content with high reproducibility. Importantly, the known two‐step kinetic process of the NCA‐ROP and the strong influence of the secondary structure on the self‐assembly process are two critical features that could significantly impact the behavior of the proposed aqueous ROPISA of NCA.…”

Aqueous Ring‐Opening Polymerization‐Induced Self‐Assembly (ROPISA) of N‐Carboxyanhydrides

“…This kinetic rate is in the range of previously measured ROP of BLG-NCAe nhanced by proximity-induced cooperative polymerization. [22] To further study the kinetics of this aqueous ROPp rocess,w ef ollowed the polymerization propagation using aq uenching method (see Mat&Meth SI).…”

“…At all solids content below or equal to t S = 13 %, particles size and distributions are essentially unchanged as compared to t s = 7% (Figure 3, Table 1). Overall, the ROPISA of BLG-NCAi nitiated by PEG 5K is af acile and robust process to prepare well-defined amphiphilic polypeptide in aqueous solution and to access their related nanomaterials at unprecedented solids content with high reproducibility.Importantly,the known two-step kinetic process of the NCA-ROP [22] and the strong influence of the secondary structure on the self-assembly process [24] are two critical features that could significantly impact the behavior of the proposed aqueous ROPISA of NCA.…”

Accelerated Polypeptide Synthesis via N‐Carboxyanhydride Ring Opening Polymerization in Continuous Flow

“…Mijalis et al sped up this synthetic approach with a revolutionary automated continuous flow-based procedure for peptide synthesis based on SPPS, reporting convenient synthesis of up 1,2-dichloroethane. [29][30][31] Additionally, organocatalysts may be introduced to increase the rate of polymerization. Zhang et al proposed the introduction of imidazolium hydrogen carbonates to accelerate the rate of reaction in DMF, accessing linear and cyclic topologies through the dosage of organocatalyst, and optional addition of amine initiator.…”