Insight into Lysine Selection via Controlled Degradation of 2,4‐Diaminobutyric Acid and Ornithine Polypeptides

The selection of twenty canonical amino acids in protein synthesis is well‐established, yet the reasons behind their natural selection remain unclear. Specifically, why structurally similar analogs, such as L‐2,4‐diaminobutyric acid (Dab) and L‐ornithine (Orn), are not chosen over L‐lysine (Lys) is unknown. These analogs differ only in alkyl chain length, raising the question of whether such variations influence polypeptide stability and natural selection. To investigate how unnatural amino acids affect the stability of synthesized polypeptides, we present the efficient synthesis of o‐nitrobenzyl carbamate‐caged photo‐responsive polypeptide amphiphiles based on Dab and Orn via polymerization of N‐phenoxycarbonyl‐functionalized amino acid precursors. Depending on the self‐assembly methods, these poly(ethylene glycol)‐b‐polypeptide hybrid block copolymers (HBCPs) formed various nanostructures, including two‐dimensional discs and oblate vesicles. Upon photoirradiation, the newly liberated primary amines in the polypeptide side chains underwent spontaneous cyclization with backbone amide linkages to generate thermodynamically stable 5‐membered or 6‐membered lactams. Such a backbone degradation process eventually led to the disassembly and disintegration of the assemblies. These findings provide new insights into the natural selection of Lys over its analogs, Dab and Orn, in proteins, and open new possibilities for creating functional polypeptide‐based materials in controlled drug delivery, tissue engineering, and other biomedical applications.