 So it's important that a protein is a polymer that means that we will not take the entropy to infinity and that means that we actually can fold But it's not sufficient because most polymers are exactly like the plastic bags They're homo polymers all the units the monomers are identical, which makes them very boring nothing special Proteins in general not this particular one But in general the amino acid side chains will be different and it's these amino acid side chains that makes protein so unique That is they are not homo polymers in general, but hetero polymers different copies of the subunits This it turns out is what's going to give the proteins the unique properties that they actually have a proper phase transition There is something that happens that phase transition It's intimately related to a free energy barrier the free energy barrier is what creates this property that you're either on the left Or the right side of the barrier you can't sit at the top of the barrier all or none If we borrow one of these schematic plots in high-dimensional landscape So what would happen rapidly when we throw that chain in water is that we're going to slide down into a multi-globul phase So we start with something that's high free energy going from coil into our multi-globul, which is a local minimum Then there has to be some sort of free energy barrier here to have a phase transition As I hinted last lecture that protein folding must be Until we find a lower free energy that is the true native state if this was not lower proteins would not fold So we want to understand the character of this barrier and why it happens in the first place and that is you entirely to the side chains So we look at those side chains. What do they look like? Well in general, this is an example from an NMR structure I think do you see that they're quite well defined and it might not be obvious here But in this particular case that the interior of the protein here is like 80% of the density of a pure liquid or solid It's very dense. Don't just the fact that we represent with this liquor sticks. It does not mean that it's full of space An easier way might be to have a molecular model where you see all these side chains The reason we have the structure of these side chains is that they are so specific that they have the exact same Rotation in billions of copies of this in the crystal So the packing in the actual native state is unique and it's the uniqueness that creates social transition And you can almost guess this already now if you're unique, that is one specific way of packing, right? I can't be in almost that state because again, it's pretty much just one state The next closest state would be if I moved out and then packed them in a different way Sure, that's closed, but I can't move over gradually to the next state There will definitely be a barrier moving up and then finding the native state And as it turns out, that's roughly where we're going to go Let me show you that in a different way One of these schematic proteins. This looks horrible, right? It's full of air inside But this is nothing like those multi-globul structures that I showed you Because here I don't show the side chains Actually, instead of side chains, let me show you a space-filling model with every single atom Boo! There is not a yota of space here anywhere. It's space-filling, literally And there is no water whatsoever inside the structure, which is very characteristic for a native state The side chains are perfectly packed. All the secondary structure is there It's unique, and there's really no second best state that we visit all the time Now, you might argue that we saw these simulations, right? Things here are certainly moving. Yes, sure, they are moving But if you look at that, for instance, the aromatic ring here Do you see that it has pretty much exactly the same confirmation? So in the sense that it will rotate just a little bit, that's fine But you're never going to see it flip 180 degrees The side chains are well packed, and it's a side chain packing That creates the unique property of a very low energy here It has to be that makes for a unique state And aren't with that, and our previous guess is how the entropy would drop It turns out that we can now understand what the barriers are