Regulating Promiscuous Catalysis via Substrate-Induced Transient Assembly

In nature, substrate-induced assembly is a fundamental requirement for a wide range of enzyme-driven chemical transformations. Systems chemists have introduced synthetic substrate analogues that have proven effective in enhancing catalytic activities of assembling peptide folds, and mimic primitive enzymes. However, how catalytic promiscuity, the ability of one catalyst to catalyse multiple orthogonal reactions, might have shaped the diversification of prebiotic chemistry, remains largely unaddressed. Herein, we report a novel transient, substrate-induced co-assembly between a lysine-rich pre-assembling peptide and Fmoc-glycine. The nanostructure formed under nonequilibrium conditions provides the suitable microenvironment to promote the potential of catalytically active amino acids, performing orthogonal hydrolysis and C═N condensation reactions. Simultaneously, carbamate bond cleavage of the labile Fmoc group destabilises the co-assembly in the activated state, causing the structure to collapse gradually. By encoding catalytic promiscuity into assembling building blocks under kinetic control, we shed light on the emergence of primitive catalysis with broad substrate scope at the origin of life.