 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 internal 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 called ACE2 receptors that are common in lugs heart blood vessels again I won't go into the pharmaceutical details here and the process works 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 these events 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 refuse 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 use 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 wait until the next slide when this happens under some conditions first you will have the outer layer of each membrane fused with each other and that means we have something called a hemifused state it's now highly curved and everything and it's 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 membranes 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 kassen who's now a professor at the university of virginia did some 15 years ago so this is a gigantic simulation of two full vesicles it's roughly one million atoms both lipids of 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 and 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 and when i hit the play 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 it would follow i can't i've 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 hemagglutinin 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 and it appears that these drill down in lack of a better word and 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 nmr experiments guesses what the structure might be but when these are drilling down here are my normal lipids pointing down if i'm perturbing the 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 this fusion peptides are exceptionally important for the virus why do we care well if you want to create antiviral drugs which is a whole topic right now not vaccines but drug that's 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 the 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