AI Used by Baker Lab to Design Proteases

Two recent publications in Nature from the Baker lab and the Institute of Protein Design at Washington University showcases the de novo design of proteases.  The first article focuses on "the de novo design of enzymes that use an activated cysteine nucleophile to hydrolyse the polypeptide backbone in a sequence-dependent manner, with a success rate of 13/69 = 19% and rate enhancements over the background reaction (k(cat)/k(uncat)) of up to 3 x 10(7)...Experimental and computational analyses suggest that the remaining gap in activity to the most active native cysteine proteases arises from imperfections in active-site preorganization and substrate positioning."

In the second article, the Baker lab "use RFdiffusion methods to de novo design proteins with water-activating zinc-based active sites adjacent to a peptide substrate binding pocket...We further design caged cytokines and receptor antagonists that are selectively activated by the designed proteases, enabling bioorthogonal control of cell state. Thus, de novo design can yield highly active, programmable proteases with applications in therapeutics, biotechnology and bioremediation."

All designed structures were crystallized through the Institute of Protein Design and their structure solved using x-ray crystallography.  Some of that work was done at NE-CAT.  Both articles were featured this month in Ars Technica, "Researchers use AI to design proteins that cut up other proteins."