Researchers use AI to design proteins that can cut up other proteins

A protein is a chain of amino acids held together by what are called peptide bonds. On their own, these bonds are extremely stable; they are estimated to have a half-life of several hundred years. But in the terrestrial environment, most proteins don’t last that long. Indeed, organisms have evolved a handful of ways to catalyze the breaking of peptide bonds, which have branched out into countless enzymes specialized in protein digestion. Proteases are everywhere and generally make short work of all the proteins that end up in the environment.

Now, researchers have fundamentally short-circuited the diversification process, using AI-based protein design tools to take the catalytic core of two types of protease and replace everything else in the protein. The resulting enzymes could be tuned to cut specific proteins in half, and the researchers demonstrated their effectiveness by using them to reduce proteins associated with neurological diseases.

Cut proteins

The basic peptide bond isn’t particularly interesting: it’s what you get when you link an amino group to an acid, releasing a water molecule. As their name suggests, amino acids have both an amino group and an acidic group, allowing them to form peptide bonds on both sides of the amino acid. This is essential for the formation of the long chains present in proteins. (Amino acids also have side chains with distinctive chemistry, which gives their backbones specific properties.)

Breaking these bonds simply reverses the process by breaking the peptide bond and a water molecule, and connecting their parts. Since both components are chemically stable, the reaction requires an enzyme to occur at any frequency. Without an enzyme, a typical peptide bond would be stable for hundreds of years in water.

Life has evolved a handful of enzymatic mechanisms that manage this catalysis. The research in question here draws on two different pieces of research. One is a zinc protease, in which the positive charge of the zinc atom coordinates the peptide bond that is broken, the key elements of the protease, and a water molecule. The protease partially removes a proton from the water molecule, activating it to attack and break the peptide bond.