Two-way mechanism of designer biomolecular condensate catalysts

24 March 2025, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Condensates formed via liquid-liquid phase separation provide a chemically versatile environment for catalysis through dynamic molecular interactions. We present designed biomolecular condensates, formed by LLPS of minimalistic histidine-containing peptides, catalyzing ester hydrolysis with two distinct mechanisms. Zn2+-dependent condensates activate a coordinating water molecule at the active site, formed by Zn2+-histidine coordination, enabling nucleophilic attack. In the absence of Zn2+, catalysis is driven by intermolecular low-barrier hydrogen bonds between histidine residues, facilitating nucleophile formation. Combined computational and experimental evidence reveals the molecular basis of these catalytic pathways, demonstrating the functionality of biomolecular condensates in catalysis and nanotechnology. These findings establish a foundation for exploring new mechanisms of metal-free emergent catalysis within complex liquid assemblies, expanding the potential of LLPS-based systems in green chemistry and advanced materials.

Keywords

liquid-liquid phase separation
biomolecular condensates
self-assembly
catalysis
enzyme mimetics
coacervates
bioinspired materials

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Supplementary Information for the manuscript "Two-way mechanism of designer biomolecular condensate catalysts".
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