Iterative Synthesis of Intrinsically Disordered Protein Mimics

Artificial intrinsically disordered proteins (IDPs) are often biosynthesized in cells by repeating low-complexity sequences derived from native IDPs through rational engineering. Herein we report the chemical synthesis of stereocontrolled linear and cyclic IDP mimics with up to 640 amino acids (∼52 kDa) via an iterative exponential growth (IEG) strategy. Following a known sequence originating from the disordered region of natural tropoelastin, linear elastin-like polypeptides (ELPs) were synthesized by conjugating monomeric pentapeptides via IEG, which transferred the sequence and chiral features of pentapeptides to the resultant polypeptides, thereby achieving robust control of their molecular weights and stereochemistry. Cyclic ELPs with different molecular weights were further synthesized via intramolecular amidation. Distinct lower critical solution temperature phase transition behaviors were observed with varying molecular weights, stereochemistry, and topology of ELPs. Our work demonstrates a new synthetic route toward chemically complex ELPs and the profound impact of chemical parameters on their properties.