 So in an ideal situation, the alpha helices we would like to insert would perfectly match the membrane. Or maybe that isn't so ideal after all. It turns out that we can learn a lot by studying what would happen in a non-ideal case. Guess about that and see if that is confirmed by experiments. So let's assume that I have a small membrane and now I'm sorry I'm going to draw this in the way you really shouldn't draw membranes. This is not how membranes look, but you don't want to have me spend the next 10 minutes just drawing proper lipid chains. What if I try to insert some membrane protein here alpha helices that are too long? They're not going to look like that because there will be hydrophobic parts here sticking out. That will definitely not happen. So if I have several helices like that, the first thing that would happen is that they would aggregate that I can draw on here. It's at least better to have three helices together this way if they mismatch so that there's only the parts on the outside matching rather than having three different parts at different positions of the membrane matching. I might also end up in a situation where these lipids somehow start to stretch out their chains a bit so that I create a longer region here where the membrane is locally a bit thicker. Again now that I just draw the chains in parallel fashion that's not going to be so obvious but remember that I said the chains are in general a bit zig-zaggy while here they would be straight. Then I might create an environment where I get these three helices to fit just perfectly and we will see that that actually happens now and then. So that's one way to stabilize this so-called hydrophobic mismatch. That's an important concept so I'll write it down. Hydrophobic mismatch. The other part that can happen is that I didn't draw this specific but there are different types of helices. Do you remember that there is a helix called 310 helix? So if I stretch the helix harder it would, that I would literally distort the backbone a bit. It's not going to be as advantageous as a normal helix but I get a slightly longer helix. So if the membrane is too thin or short I might be able to alter the backbone of a helix. So 310 helix would be slightly longer or in this case I would prefer a so-called pi helix so that I make the helix itself slightly shorter to fit the membrane. The other part that could happen if I'm still thinking about too long helices I could take my membrane, let's see here I need to do the math correctly here. Slightly fewer lipids here and take that entire helix and draw it in a tilted fashion. That would also enable you to keep a longer helix in the membrane without distorting the lipids too much. You can probably imagine that this is going to be pretty bad because it's now distorting the lipids instead. But maybe if I have five or six of these together it could stabilize things a bit. If you look back at that bacterial rhodopsin structure you will kind of see that a few of those helices are tilted a bit so that makes sense. The same way we can consider what happens if we have helices that are not really thick enough. There too you could have an aggregation effect that if we anyway need shorter lipids it's not ideal but it's at least better to have three short helices. It's at least better to have three short helices together than at different places. The other alternative we can assume here we can have the membrane curl up even more. Here I will actually draw zigzaggy chains. I'm not good at drawing lipids. You see here by making the chains zigzaggy I effectively create at least a locally thinner membrane that could then match my helices. And here too I might be able to stretch out the backbone of the helix itself to make that slightly thicker. The other thing I just might be able to do is that if nothing else works if the helix is simply not long enough to go through the membrane well at some point I will have to give up. And by giving up I mean that the helix will eventually sit on just one side of the membrane. It will become a sort of interfacial helix. That's going to be bad for other reasons. In this case I'm going to need half the helix here to like water and the other half of the helix to like the membrane but again if I don't have any other choice. The key take-home message here is that do you see how lipids can adapt to the protein for instance here but you also have the protein adapt to the lipids and I'm going to keep coming back to that. It goes both ways. The problem though here is that this is just based on my hand waving. You have no idea whatsoever if this is true. And I can't really determine x-ray structures of this because we're looking at transient features of lipids floating around in individual, transient features of protein floating around in lipid environments. I can't crystallize that lipid environment. It is possible to access this indirectly in particular with NMR, Nuclear Magnetic Resonance and Antoinette Kilian and Ole Moritzsen spent almost 15 or 20 years on this in the 1980s. I'll come back to that in a second and show you how they did it but basically they systematically try to replace residues here and see what happens. At what point will we start to have tilting in the helix for instance. But before that let's look at what this would do to a real protein.