Molecular Self-Assembly Strategy for Generating Catalytic Hybrid Polypeptides.

Area of Science:

• Biomimetic catalysis
• Peptide self-assembly
• Enzyme engineering

Background:

• Catalytic peptides mimic natural enzyme activity, showing promise in organic solvents.
• Low catalytic efficiency in peptides is attributed to the lack of stable tertiary structures.
• Natural enzymes achieve high efficiency through specific active site configurations.

Purpose of the Study:

• To enhance the catalytic efficiency of peptides by promoting self-assembly.
• To investigate if incorporating hydrophobic pockets into peptide structures improves activity.
• To design self-assembling peptides that mimic enzyme active sites for improved function.

Main Methods:

• Fused catalytic peptide CP4 with an amyloidogenic peptide fragment (Aβ).
• Induced self-assembly of the CP4-Aβ construct into antiparallel β-sheets and amyloid fibrils.
• Assessed the hydrolysis rate of p-nitrophenyl acetate (p-NPA) for the assembled peptide.

Main Results:

• The self-assembled CP4-Aβ construct exhibited a 4.0-fold increase in p-NPA hydrolysis rate compared to the neat CP4 peptide.
• Enhanced activity was linked to the pre-organization of a catalytic Ser-His-acid triad.
• Hydrophobic stabilization of the substrate within the assembled structure contributed to increased catalytic efficiency.

Conclusions:

• Self-assembly of catalytic peptides into amyloid structures significantly enhances catalytic activity.
• Designing peptides with integrated hydrophobic pockets can mimic enzyme active sites effectively.
• This strategy offers a promising route for developing efficient and functional biomimetic catalysts.