 Hopefully you've studied amino acids by now, but that's going to be where we have to start. The amino acids and proteins, that's going to be the stuff that interacts with the membrane. Gunnar and a few others will talk a little bit about membrane insertion, which is a complicated process in itself. But if you trust me that the backbone of say, helices can insert in membranes, that's going to mean that the entire difference will come from the different properties of different amino acids. And that's entirely due to the side chains. That's the one difference we have. In particular, we have some non-polar aliphatic groups, like smaller side chains. Alanine is not quite non-polar, but it's small enough to the side chain is effectively non-polar. You have valine, leucine, isoleucine, etc. They're great in the cells that they don't have any large aromatics rings. It's a fairly floppy, flexible chain, and there are pretty much no charges at all in the chain. They're going to love to be in the membrane interior. We have some polar side chains. They're not charged, but they are polar. They will not love to be in those lipids environment, but they might be able to get by. They're under some circumstances, but they will likely prefer the head groups. Then we have, on the other side here, you have positively and negatively charged side chains. There is no way they're going to enter the membrane, at least not under normal circumstances. They will need to be in the head groups facing water. Then we have some special cases. For instance, the aromatic side chains. Some of them are hydrophobic. Some of them might have one hydrophobic and hydrophilic part, which makes them very interesting because they could kind of like both the head groups and the tail region of the lipids at the same time. That's going to help us. I think the best way to illustrate that is to go back to our friend the lipid. I have to confess that this is not an isolated lipid. If this was isolated, the chains would stretch in both directions here. But this is a snapshot of one lipid from a large membrane running in a simulation. It's just that I've hidden all the other lipids for you. But if we consider a simple side chain, such as valine, where would this valine molecule like to go? Well, the entire side chain here is hydrophobic. I actually could not put that amino acid the way it looks here in a membrane because the zwitterionic backbone here, right, the nitrogen and the oxygens, they would have very large charges. But if we presume that those were part of a helix, these parts would literally be part of the helix and have hydrogen bonds to other partners. And then we could kind of cut this off. So I only have to consider the side chain. That side chain is going to love to interact with the lipid chain. So roughly from here up to here. It's going to be soluble like salts like. And in particular, there's not going to be any hydrogen bonds perturbing or anything. Beautiful. Another side chain that we considered the same way. Again, let's forget the backbone part. This is arginine. It's a beautiful side chain in many ways. But in terms of solvating it inside membranes, it's as horrible as it gets. You have plus one charge here, typically. That charge is going to mean that there is no way it's going to go here. This will have to interact with the head group region. In particular, the phosphate there, that's negatively charged. Or even those carbonyls, you have the oxygens here. Oxygens typically have negative partial charge in molecules. So that will likely be a place where that one likes to interact. Then on the other hand, we could pick something more complicated. Tryptophan. It doesn't get larger and more complicated than that in terms of amino acids. Where will this side chain want to be? Well, you have the hydrophobic part here that would likely prefer to be down here. Then you have this part here, right? The NH group. That's going to be polar. So that would prefer to be up here. So this molecule would somehow prefer to be maybe oriented this way. So that the polar part can interact with the head group and the hydrophobic part can interact with the chains. And that means that we will not really be able to push this either down or up. So it's kind of like casting an anchor here. In addition to that, do you see how large this side chain is? It's going to be virtually impossible for this side chain to start to rotate. Because remember, I'm surrounded by these lipid chains. There are several other lipids that I've hidden here. So this side chain will have to be placed like my hand this way, so that it can intercalate, squeeze in between two lipid chains. If I were to place it that way, it would cut straight through like half a dozen lipid chains. So this is going to be a very particular side chain that both is ordered and it stays put in one place. I will come back and show you that in a few lipids. So already here, we start to see that there are patterns with which how amino acids interact with lipids. And in particular, different amino acids will prefer different parts of the lipid environment.