Conserved catalytic motifs encode enzyme-like supramolecular peptide assemblies
TL;DR
The findings establish conserved catalytic motifs as a rich source of functional catalysts and demonstrate that they encode sufficient information to construct highly active supramolecular active sites independently of the globular protein fold demonstrate that complex catalytic function can emerge from remarkably simple self-assembling peptide architectures.
Abstract
A seven-residue fragment derived from the active-site region of carbonic anhydrase spontaneously forms Zn2+-binding amyloid fibrils that catalyze carbon dioxide hydration with catalytic efficiencies surpassing all previous carbonic anhydrase mimics and approaching those of natural enzymes. Cryo-electron microscopy at 2.2 Å resolution, supported by perturbed angular correlation spectroscopy, solid-state NMR, molecular dynamics simulations and QM/MM calculations, reveals a supramolecular active site that recapitulates key structural and mechanistic features of the enzyme despite arising from a fundamentally different protein fold. Guided by structure–activity relationships, minimal sequence modifications fallowed for further optimization to reach carbon dioxide hydration activity of 1.3 × 106 M−1 s−1. Extending this strategy to a conserved motif from superoxide dismutase yielded copper-binding catalytic amyloids that promote superoxide dismutation near the diffusion limit. Together, these findings establish conserved catalytic motifs as a rich source of functional catalysts and demonstrate that they encode sufficient information to construct highly active supramolecular active sites independently of the globular protein fold. More broadly, they demonstrate that complex catalytic function can emerge from remarkably simple self-assembling peptide architectures, providing an experimentally tractable framework for investigating the fundamental principles that underlie enzymatic catalysis.