How Does Leash Bio Find Binding Chemicals?

Ian Quigley says Leash Bio finds binding chemicals by fixing a protein target on a magnetic bead, dunking the bead in a barcoded mixture, and sequencing the DNA that stays stuck after a rinse.

The target is a protein or a protein complex on a solid support. Leash Bio usually uses a magnetic bead. Amino acid chains click onto the ends of each other, fold, and either bind the target or miss it, and each component carries a barcode. In an easy case the protein has a distinctively shaped hole. A tiny fraction of the chemicals have the shape and electronics to fit the hole. The protein is pulled back out and rinsed a couple of times, so only the chemicals in the hole come along. A little PCR amplifies the barcodes, and the sample goes into a sequencer.

Relative enrichment needs negative controls: the bead by itself, and a check for pan-protein stickiness that pulls certain chemicals from the library anyway. Subtle biases might make some DNA amplify faster than other DNA during PCR, so a short unique sequence marks copies from one binding event and lets them collapse together. At Leash, some proteins stick to DNA because that is their job, so barcode design has to account for it.