Regulation of Chemical Transformation in Designer Peptide Biomolecular Condensates

Abstract

Biomolecular condensates, formed through liquid–liquid phase separation, serve as dynamic platforms for biochemical regulation. Inspired by these natural systems, we develop designer peptide-based condensates to modulate chemical transformations, focusing on the Cu(I)-catalyzed azide–alkyne cycloaddition click reaction between hydrophobic reactants as a model system. By incorporating a varying number of isoleucine residues into peptide sequences, we tune the hydrophobicity of the condensates. This variation allows us to tune condensate properties, including reactant recruitment, internal mobility, and catalytic performance. We show that peptide hydrophobicity dictates selective partitioning of the hydrophobic azide reactant into the dense phase, while increased hydrophobicity reduces internal diffusion. Higher molecular mobility within the condensates correlates with increased reaction rates and product formation, leading to enhanced spatially localized reactivity within the condensates. Together, our findings establish a mechanistic framework linking the peptide sequence, condensate dynamics, and compartmentalized catalysis. This work provides a foundation for using designer condensates as programmable microreactors for sustainable chemistry and biomedical applications.