 So the obvious way to understand how a membrane protein interacts with the membrane that would be to just determine the structure of the membrane protein The problem with that is that there are two problems first is really really really difficult to determine structures of membrane proteins second When we actually do that in the few cases we do the only reason we manage is that we typically take them out of the membrane and put Them in a much simpler environment That simpler environment is not really going to help us understand the original lipid interactions that much But we have to start somewhere The one of the first membrane proteins people studies was bacteria rhodopsin Rhodopsin this is an exceptional interest in class of proteins But in the interest of time I won't take you through exactly what they do But it's very similar to the rhodopsin molecule we have in our eyes. That's detecting light Bacteria rhodopsin occurs in bacteria in particular in a membrane called the purple membrane and the membrane is so stuck with Proteins that it's like 50% of the mass here is protein rather than lipids. So it's almost like lipids embedded in protein That made it a great candidate to try to stabilize Hartmut Michel came up with a great idea that you can rip this out of a membrane and stabilize it pretty much with detergent I'll come back to that at the very end of the lecture So you don't have to understand why for now Then you could turn this into a crystal and you could ground the crystal down If you ground the crystal down that's where you see this purple color It actually comes from the mixture of the protein and lipids. That's why we call it the purple membrane and Based on that they were eventually able to determine the structure of the first membrane protein And they got a noble prize for this discovery too that you could stabilize membrane proteins The structure itself consists of seven alpha helices Trans membrane so they go from one side and then a small loop out to the other side small loop down to the other side That this makes a lot of sense The alpha helix is going to be a very nice stable structural element because all those peptide bonds You know about they would they are polar they would normally hate to face the lipid environment But this way they face each other you form hydrogen bonds in each alpha helix Hydrogen bonds to the second alpha helix Beta sheet proteins. Well, there are a few membrane proteins that are beta sheets But in general we could not put a beta sheet in a lipid environment because the end of the edge of the beta sheet would face the lipids, right? The only way we do manage that is by turning the entire beta sheet into a barrel and closing it up on itself So there is effectively no edge But this when this first appeared we were excited that it's simple We just need to understand these helices and then if the helices pack we should be able to understand how membrane proteins work In practice it turned out to be a little bit more difficult, but we haven't quite reached that part of history yet So let's just be content and assume that this is going to be something easy to understand You might think that if you remember globular proteins, how are globular proteins stabilized? globular proteins are stabilized by having hydrophilic water-liking residues facing the outside and then you have a rapid Hydrophobic collapse where the hydrophobic residues will face the inside So if I draw that to you in water You would rapidly have a chain here where you had some positive and negative charges and some hydrophobic ones that would Rapidly go to the state. We have all the hydrophobic parts on the inside while the charges are on the outside important part of protein folding When we first saw these proteins first you realize if the lipids are entirely hydrophobic and then you see the amino acids You're a ton of them are hydrophobic So some of the first simple models were that membrane proteins were kind of the opposite it makes sense if that's Hydrophilic on the outside hydrophobic on the inside these should be hydrophobic on the outside and then maybe hydrophilic on the inside Unfortunately, that's not quite true membrane proteins tend to be hydrophobic everywhere or let me modify Membrane proteins tend to be hydrophobic everywhere in the parts that go through the membrane with a few exceptions I'll come back to these parts on the other hand can be quite hydrophilic and as Gunnar will tell you There are going to be patterns here when in general we tend to have positive residues on the inside Which determines how they sit in the membrane? That makes membrane protein folding exceptionally difficult to understand Gunnar will spend an entire lecture on it I think I will touch a little bit on it But it means that the stabilization of membrane proteins is much more delicate than water This will to first approximation just be Lenard Jones packing thunder balls interactions There are gonna not gonna be any hydrogen bonds keeping things together in general These healers is just diffuse and find each other and hopefully they pack well enough that they will maintain their stability the membrane helps with this because the Hydrophobic hydrophilic parts of these head groups means that I can't take this protein and pull it out of the membrane Then I would expose hydrophobic parts I also can't move it down because this hydrophilic regions here would then be exposed to the lipid environment So there is a symbiosis here The membrane helps stabilize the protein and the protein might help create a bit of a structure in the membrane as we will see