 So given how much we've spoken about myoglobin and hemoglobin, I think it's time to look at them. This is hemoglobin, the big molecule. Four subunits, the small red ones are the oxygen-binding heme groups. Probably easier to see if we divide it this way. Here you can probably see that it's a dimer of dimers. And if I color each chain separately, it's gonna look like this. So we have one, two, three, four chains and then the heme groups with their iron in red. In your blood, hemoglobin exists as the tetramir. We'll come back in a few lectures and tell you why it has to be a tetramir. But we could decide to look at just one of them. In this case, I have to confess that this is actually hemoglobin, but there is a very similar protein called myoglobin. That is pretty much just one of the subunits from hemoglobin, not expressed from the same gene. What these have in common is that they have six helices, roughly. A few species might have an extra small helix at the beginning or end, but the central part here is six helices. They're organized in roughly a hexagonal shape. Sorry, not hexagonal, tetrahedral shape. So there is a small tetrahedron and this is hard for me to draw, but I'm gonna try anyway. So if this is the base of the tetrahedron, the triangle, you have three sides there, right? And then I have one side here and then one in the rear and one side here. There's one, two, three, four, five, six sides, or edges. These create a nice, small cavity on the inside and this cavity on the inside is where you have the red protoporphurin group binding the iron, which is yellow here. When that iron undergoes a reaction between ferrous and ferric form, it will have an ability to bind the oxygen or not, which is gonna cause the entire ring to tilt a little bit and then the entire protein will go over in a slightly different shape and then later on it can also release the oxygen. There's gonna be a special interplay when we have four of these that I will come back to, but already now I'm gonna wet your appetite a little bit. I told you that we don't want the protein that is too good at binding oxygen because it has to be able to deliver the oxygen to the lungs. So the reason for this one versus multiple subunit is related to when we're carrying oxygen in the blood versus when we're carrying or binding oxygen in the muscles. The protein that binds oxygen in the blood has to be able to take up oxygen from the lung, but it also has been able to hand off and deliver it to this other protein that exists in our muscles. I'll tell you about that when I talk about structural transitions. This protein is a poster child. It was the first folds that we discovered. John Kendrew and Max Peretz were working in parallel in hemoglobin and myoglobin and they shared the Nobel Prize for this in 1964. I think it was. It's not a strict tetrair, right? Tetramir, sorry, it's not the strict tetraedron and hemoglobin itself is a tetramir while myoglobin is a monomer. Let's have a look at that particular protein is constructed. I'll erase this one quickly first. Remember when we spoke about genes, these helices are constructed from a fairly long gene and it's the fact a gene that has introns and exons. Do you remember what introns and exons were? In vertebrates, higher eukaryotes, we have this pattern in DNA that not all bases in DNA correspond to amino acids that will show up in a protein. But we have a blue part here that's an exon and then an intron and then an exon and then an intron and then an exon, intron, exon, intron, exon, many of them. What happens in the DNA is that the transcriptase will read that from the DNA, but then we're stitching things together that we're deciding here is an exon or weight. We get an intron. We don't want that intron material. So we're going to remove that intron material and stitch the blue part here together with the green part. So once this is turned into mRNA, messenger RNA, the introns are really no longer around. It's just the exon parts. So if we translate this to these multiple helices in myoglobin or hemoglobin, it makes a lot of sense, right, that each exon should correspond to a secondary structure element. That's a sound. It's a simple idea. The only problem is that it's completely wrong. And that's important to remember. These three exons we have for the domain and start looking like this. So the first red one is a helix and a half. The break between two exons here happens right in the middle of one helix here. So here in the DNA, you would actually have a bunch of other intron bases that have been cut out. And then I have another two, well, half a helix, two full helixes, and another half helix. And then I have another break again. So there is no relationship whatsoever between the positioning of introns and where your secondary structure elements are. Exactly why we're still not entirely sure, or rather we are sure that by the time we start folding a protein, the introns are no longer around. Remember, already the mRNA, the introns are gone, period. So by the time the mRNA gets to the ribosome, we've long since lost all memory of the introns. We have no idea that they were in introns. So in a protein folding way, it makes sense that it can't matter where the introns were. On the other hand, in DNA, why the introns occur in those special places, that's a bit stranger. We're going to talk a little bit about how nature does mutations in DNA later on. It would have made a lot of sense to be at least to figure that the mutations happen one secondary structure element at a time or something, but that's not the case. It's more complicated. So what do we use those introns for? Well, that's a separate chapter in this class, which is actually great given that we don't really know yet. So only a few years ago, this was published in Nature. And again, you should be a little bit cautious here because this is still research happening. It's not settled science. It's not broadly agreed knowledge. But the thesis here was really that introns are mediators when cells starve and basically helping cells adapt to a changing environment. And there are a few other examples like that where cells somehow they change their expression in different conditions. A great example of that is also hemoglobin, actually. A llama has different hemoglobin from me. And a fetus has different hemoglobin from an adult. Think a little bit about why, and then we'll come back to that in the bioinformatics class or bioinformatics lecture. For all of these helices in hemoglobin and myoglobin, we're going to use this fact in limited number of ways we could pack helices. And this is the reason why at first sight, the protein might appear a bit messy. It's not messy. Remember what we said. Helices will not line up perfectly like that. That would be a very disadvantageous structure for them. Instead, they're going to line up that's roughly 10 degrees or so. This is much better. To us, it looks worse, but that's just because we're not showing you all the side chains and ridges. Now, when we have six proteins like this, that's why you end up with these complicated, globin-like folds. It appears as if the helices are almost just thrown together. Look at this in the protein data bank. Look at the structures that I showed you. There was a reason why I started out with those big blobs where I showed you the entire surface. Did you see any holes in that surface? No, you didn't. It's a perfectly packed surface. So considering every single atom, it's an exceptionally well-packed structure because nature has optimized this so that each pair of those six helices cross each other at one of these advantages' angles. It turns out you can actually make some structure in that. We have 100,000 protein structures in the protein data bank or more by now. If we just calculate the structure, it turns out that there are two very clear peaks if we calculate the crossing angles that pair-wise helices, they tend to cross each other exactly at these two angles that are advantages for the packing. And that's definitely the case in Mayo and Hemoglobin.