So some of the stuff I've told you today might be fundamental research questions and everything, but just to drive home the message that there are some very direct pharmaceutical applications here, I'm going to show you two, maybe even 2.5. Viruses in general are sadly very much on topic right now. Viruses is a very simple organism, I won't take you through the entire class on them, but briefly a virus works by somehow delivering its internal genetic material to my cells, so that my cells produce more viruses. And for that to happen, they need to find my cells, anchor to them, and somehow create the delivery. This particular virus, it's the COVID-19 virus, SARS-CoV-2. In turn, it looks something like this schematically. You have these red spike proteins that are the anchors that find my receptors. Then you're having some sort of coat, a lipid environment here, and then you have the internal interior where they have the RNA, which is very fragile, and that the virus wants to protect. The way this protein attaches to my cells, the COVID protein in particular is by attaching the, so AC-2 receptors that are common in logs, heart, blood vessels. Again, I won't go into the pharmaceutical details here. And the process works by, by first literally anchoring the protein there, it will undergo a sequence of changes to somehow deliver its genetic material into the host cell. The exact sequence of this sequence will depend a bit from virus to virus, but schematically it's roughly the same for all of them. So first, you need to anchor yourself to the host, otherwise you will diffuse away, and then on average you would never fuse, because it takes a while for fusion to happen. Second, when you're anchored, we have to tighten that anchor so we push away the water and really have full opposition. The membranes should be right next to each other. Ideally, you would somehow like to kick the host door open a bit, maybe perturb the structure of the cellular membrane a bit, because normally the cellular membrane would be self-repairing, right? They would not fuse, but if they're a bit perturbed, at some point they might start to heal against each other, so that these two become one membrane. That's deliberately a bit fussy weight until the next slide. When this happens under some conditions, first you will have the outer layer of each membrane fused with each other. That means we have something called a hemifused state. It's now highly curved and everything, and the interiors are not yet in contact, but this is an intermediate state that is somewhat unstable, so usually a short while later we have full fusion, and then we're in the lower right here, and at the full fusion situation I can deliver my RNA if I'm a virus to the host cell interior. The way this hand waving part in the middle works is usually by having some sort of method to increase the probabilities of the membrane fusing. I'll show you that in a second, but first I'm going to show a schematic movie that a former postdoc actually at the time, Peter Casson, who's now a professor at the University of Virginia, did some 15 years ago. This is a gigantic simulation of two full vesicles. It's roughly one million atoms, both lipids and water here, two full layers, and then a similar three-dimensional vesicle here, also one million atoms. It's too expensive to include all the proteins in everything here, but what Peter came up with, he's adding a small chemical linker, with roughly 10 bonds, or so, to force them to stay together. When I hit the pay button here, you will see quickly that they push the water away, the head groups are interacting, and then you're going to see that the first two layers fusing, and the short while after that you saw the inner layers fusing too. It was a bit fast, but you probably agreed that it followed all the mechanical steps that I hinted that it would follow. I kind of seen the movie already. The way the two membranes are actually encouraged to fuse, we don't know that exactly, but we somehow know that there are certain proteins, hemagrythinine if it's flu, that contains small segments of amino acids that are semi-hydrophilic, semi-hydrophobic. They seem to prefer to go into the membrane, but they're not really transmembrane helices. It appears that these drill down in lack of a better word in the host cells membrane, and then they perturb that structure a bit. We again, we don't know exactly what the structure is. These are based on anMR experiments, yes, is what the structure might be. But when these are drilling down, here are my normal lipids pointing down. If I'm preserving this structure, at some point I might have a lipid or two pointing sideways. And if I have the same type of perturbation in my viral membrane here, at some point the hydrophobic parts here will start to get in touch, and that is really going to be the part that initiates the actual fusion. So these fusion peptides are exceptionally important for the virus. Why do we care? Well, if you want to create antiviral drugs, which is a hot topic right now, not vaccines, but drugs that specifically bind to a compound on the virus and would inhibit its function. First, you could try to find something that might inhibit the fusion peptides, but even if you do manage to find something which might not be that hard, viruses mutate so far. So they will likely very quickly have a new strain that is no longer sensitive to that one. But the trick with targeting the most important functional regions of the virus is that if the virus, the virus is exceptionally dependent on the sequence in this fusion peptides for fusion to happen. So the virus does not have so much freedom to mutate away and change this to anything it wants. Well, it can change them, but then it's no longer going to be as infectious. So targeting regions of viral fusion proteins that are important for the fusion itself is likely a very good strategy to develop new antiviral drugs.