A protein is a chain of amino acids held together by so-called peptide bonds. Individually, these bonds are extremely stable; Their half-life is estimated to be several hundred years. But in Earth’s environment, most proteins don’t last nearly as long. That’s because organisms have evolved a handful of methods to catalyze the breaking of peptide bonds, which have evolved into countless specialized protein-digesting enzymes. Proteases are everywhere and generally make short work of any proteins that enter the environment.
Now researchers have essentially short-circuited the diversification process, using AI-based protein design tools to take over the catalytic core of two types of proteases and replace all of the rest of the protein. The resulting enzymes could be tuned to cut specific proteins in half, and the researchers demonstrated their effectiveness by using them to cut proteins linked to neurological diseases.
Cutting proteins
The basic peptide bond doesn’t look particularly interesting – it’s formed when you attach an amino group to an acid, releasing a water molecule. As the name suggests, amino acids have both an amino and an acid group, which allows them to form peptide bonds on two sides of the amino acid. This is crucial for building the long chains found in proteins. (The amino acids also have side chains with distinctive chemistry that give the backbone specific properties.)
Peptide bonds are formed by the removal of a water molecule from parts of an amino group and an acidic group.
Image credit: Wikimedia Commons
Peptide bonds are formed by the removal of a water molecule from parts of an amino group and an acidic group.
Image credit: Wikimedia Commons
Breaking these bonds simply reverses the process by breaking the peptide bond and a water molecule and joining their parts together. Since both components are chemically stable, the reaction requires an enzyme that can occur at any frequency. Without an enzyme, a typical peptide bond would be stable in water for hundreds of years.
Life has evolved a handful of enzyme mechanisms that control this catalysis. The study in question was based on two different ones. One of these is a zinc protease, in which the positive charge of the zinc atom coordinates the peptide bond to be broken, important parts of the protease and a water molecule. The protease partially removes a proton from the water molecule and activates it so that it attacks and breaks the peptide bond.
