Catalytic peptide-based coacervates for enhanced function through structural organization and substrate specificity.

Area of Science:

• Biochemistry
• Chemical Biology
• Materials Science

Background:

• Liquid-liquid phase separation (LLPS) is crucial for cellular organization and function.
• LLPS enhances enzyme catalysis but its role with catalytic peptides is unexplored.
• Catalytic peptides offer simpler alternatives to enzymes but often suffer from conformational flexibility.

Purpose of the Study:

• To explore the application of LLPS, specifically coacervation, for enhancing catalytic peptide activity.
• To design and create self-assembling peptide-based microreactors.
• To investigate the mechanism by which LLPS impacts peptide structure and function.

Main Methods:

• Induction of reversible biomolecular coacervates using a flexible catalytic peptide (P7).
• Characterization of the structured peptide domains formed within the coacervates.
• Assay of catalytic activity for phosphate ester hydrolysis and protein sequestration.

Main Results:

• Coacervation successfully constrained peptide conformational flexibility, forming structured catalytic domains.
• The peptide-based coacervates demonstrated efficient hydrolysis of phosphate esters.
• A 15,000-fold increase in catalytic efficiency was observed compared to soluble peptides.
• Selective sequestration of phosphorylated proteins by the coacervates was achieved.

Conclusions:

• LLPS, via coacervation, provides a simple yet powerful method to enhance catalytic peptide performance.
• Single peptides can self-assemble into functional microreactors, recruit substrates, and catalyze reactions.
• This work offers insights into the evolution of chemical functions and enzyme activity, particularly in prebiotic chemistry.
• LLPS effectively manages conformational heterogeneity in short peptides, a key factor in functional evolution.