# Regulating Promiscuous Catalysis via Substrate‐Induced Transient Assembly

## TL;DR

Scientists discovered a new way that enzyme-like reactions can happen through temporary structures formed by peptides and substrates, which could help explain how early life chemistry evolved.

## Contribution

The study introduces a transient, substrate-induced co-assembly system that exhibits catalytic promiscuity under kinetic control.

## Key findings

- The co-assembly of a lysine-rich peptide and Fmoc-glycine promotes hydrolysis and C═N condensation reactions.
- Carbamate bond cleavage destabilizes the co-assembly, causing gradual structure collapse.
- The system demonstrates catalytic promiscuity under nonequilibrium conditions, relevant to prebiotic chemistry.

## Abstract

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.

We report a novel substrate‐induced transient co‐assembly between a short Lys‐rich peptide and Fmoc‐Gly‐OH. In the activated state, the assembly exhibits promiscuous catalytic activity through the rate enhancements of hydrolysis and C═N condensation reactions. Over time, the substrate Fmoc‐Gly‐OH is cleaved into smaller fragments, leading to the collapse of the hydrogel and a decrease in catalytic activity.