Computational design of metalloproteases.

De novo designed metalloproteases achieve up to 10^10-fold acceleration of peptide bond hydrolysis and selectively cleave disease-related proteins with rate enhancements up to 10^9-fold.

• Why it matters: Designing enzymes that efficiently cleave amide bonds remains a significant challenge, limiting therapeutic and biotechnological applications. Developing highly active, programmable proteases could transform treatments and bioengineering strategies.
• What they did: Using RFdiffusion methods, 135 proteins were designed with water-activating zinc active sites near peptide binding pockets; 36% catalyzed substrate cleavage, with the best design surpassing 10^8-fold acceleration.
• The result: The approach enabled creation of metalloproteases that selectively target human disease proteins and activate bioorthogonal molecules, opening avenues for therapeutic, biotechnological, and bioremediation applications.