 Our next fibrous protein is called collagen, and we're going to meet an old friend here, Proline. Collagen is actually helix, but it's a helix very different from many helices you've seen. Here's what it looks like. Do you see all those rings? Those rings are Proline residues, but I said that Proline was a helix breaker before. Proline definitely is a helix breaker, but Proline is an alpha helix breaker. This is completely different. This is not an alpha helix. Do you see? So you have... there are no hydrogen bonds in these helices. Each individual backbone here is just moving up, and then there are some hydrogen bonds between the three backbones. So in this particular case, you have a sequence that is roughly glycine, Proline, glycine. In each of the chains, the two chains, the three chains here are actually not exactly identical. There's two similar ones, and then a third that is slightly different in sequence. There is not a single hydrogen bond inside each helix here, in particular because the Prolines can't form as many hydrogen bonds, and if you had an isolated backbone or helical strand, whatever I should call them here, that would be... they would likely be extremely floppy and flexible because there is no inherent structure. But when you place them like this together, do you see that you can suddenly form hydrogen bonds between the three chains? And this creates a so-called collagen helix, or collagen helix triplet with two plus one chain, two are identical, and one is different. These three will then form a super helix. Let me show you. Now you have these chains here. The chains are paired up three and three, and then you have a number of these three chains forming a larger super helix here. This is a recurring theme. We already saw that when we talked about, I told you about super secondary structure, tertiary structure, right? That we make sense of things by organizing it hierarchically, but you could also argue that nature has utilized evolution to be able to encode for large structures with very small building blocks simply by reusing these building blocks to form hierarchical structure. Again, the only information we need here is really glycine, proline, glycine. And yet the structure itself is much larger than the gene coding for that. This you will find in say your bone, your hair. It's probably a quarter of the bone and hair and have a structure and teeth, too, would be collagen. It's a very potentially very rigid body. Again, imagine teeth, and the reason for that is all those hydrogen bonds between the helix is here. It's going to be very difficult to break this up once it has formed. That individual triple helix might be ballpark of one and a half nanometer wide or so. And this would probably be what could it be four nanometers or so. The length of this one would be, well, maybe five hundred nanometers or so. So it's very very long, far longer than I'm showing you on the slide here. This is essentially a quaternary structure, right? So now you had first you had three helices. They formed some sort of let's call it tertiary structure, and now you had even larger things aggregating together. Even these are going to aggregate together because four nanometers is not a whole lot. They're going to aggregate together in larger and larger fibrils and proto fibrils and everything to form things all the way until we start seeing them and then they say in an electron microscope. This is a piece of dentine, which is a collagen-rich material in your teeth. What happens now, if instead of those GPG motive, what if you had a mutation here? So let's replace one of those glycines for something else. Well, you might imagine that the glycine is not important because the glycine is so small and flexible. But remember that proline is really difficult to get to fit anywhere. So we need those glycines in the collagen helix to be able to fit the proline so that they depend on each other. But if we're now replacing at least one of those glycines with something else, we will not be able to form as many hydrogen bonds here, or at least this will not be quite as efficiently packed and the hydrogen bonds will not be as strong. The free energy of it is not going to be as good. So that will mean that these structures that in the wild type without the mute were so strong and nice and rigid, they're now going to be able to break and that happens. It's called brittle bone disease. So again, brittle bone disease is caused by one mutation in collagen turning one of your glycines into an X. So we said turn glycine into an X. That means that we're breaking the beautiful regular pattern. So even glycine per se is flexible, but you need the flexibility for proline to form the strong structure. And surprisingly, if we were replacing say glycine with alanine, which in theory you might think is more rigid, the structure itself is going to go in the opposite way because now we can't pack it. It's going to be less rigid and it's brittle bone disease. It's not really a whole lot we can do about it. Today, sometime in the future we might be able to do gene technology and basically replace these genes in your body. I'm going to talk a little bit about that when we talk about drug design. But there are very few examples for this work today. There are a handful of exceptions, but in general it's going to be in the future. We can't change genes systematically and repeatedly in your body yet.