Some years ago, I think quite long... almost twenty years ago... there were the first three-dimensional structures of protein molecule. Well the first, of course, was Max Perutz with haemoglobin and John Kendrew with myoglobin and they got the Nobel Prize for that. But very soon other molecules were looked at using the X-ray diffraction method, which was pioneered in Cambridge in the school of Bragg. And among them there was David Blow, that time in Cambridge, who determined the structure of a pancreatic enzyme, so that's trypsin and chymotrypsin. A pancreatic enzyme is an enzyme which is used in metabolism of food and in this very special case it's a protein which... it's an enzyme which degrades protein molecules, so it hydrolyses a peptide bond. Now the wonderful result he got from it was not only that he could determine each atom in this three-dimensional structure within an angstrom or a fraction of an angstrom precise, what came out is a great insight into the catalytic mechanism. The catalytic mechanism was to be a proton relay, in other words there was a spatial conformation of three amino acids, one being a proton donor. That was serine, it has an OH group so, where the proton can dissociate it will do so in the basic range, so at neutral it will be still the OH group but if you go up with your pH it will be an O^- and the proton will come over. At the other end there was an aspartate, that is the carboxylic group like in acetic acid, so that is the proton of that group dissociates already in the acetic range, that means two pH values below neutrality or even three... two to three pH values. That means under neutrality where the enzymes work you have always the de-protonated carboxylic group – COO^-. And here the protonated hydroxyl group, and in between there was a histidine which has an imidazole ring and the imidazole ring has two nitrogens, one being protonated, the other not. So... and its pK_a is at 7, at neutrality. So, at neutrality you have either the imidazole ring protonated, and you have two protons and a plus charge on, so the hydroxyl group can give off its proton to the imidazole and the other proton of the imidazole hops to the carboxylic group. That's a proton relay, you shuffle forth and back protons and then you can make a very efficient acid base catalysis, because it's a hydrolytic reaction. And that makes the splitting of the protein bond, wonderful mechanism was known and very satisfactory.