 The voltage gate that I in channels are showed you are equally important in resistance. You remember this fourth helix with several charges that had to move up and down in the electric field to open a channel to potassium. These four charges here are sometimes mutated. So one of the arginines might turn into glutamine for instance and then the helix is not going to move up as easily and that leads to disease. There are two types of diseases that are common here. One of them is a heart arrhythmias and they often have names based on the shape in the electrocardiogram. Long QT syndrome is a common one for instance. Others show up as epilepsy, very delibitating handicaps due to our nervous system not working quite the way it should. In particular among children this is something we would like to treat so that it doesn't become a lifelong handicap. The problem is that it's not easy. If it's a simple plug and the channel is open too much then I can literally just add a plug in the pore to force the protein not to let through so many ions. But how do I add drug that is forcing the protein to let through more ions? I would need to find a way to literally grab that S4 helix and lift it up a bit more. Not easy. I have colleagues in Linköping, Fredrik Lindr and Sara Linn that have spent several years on this and they have eventually found some molecules that have effects here. And the molecules they're adding are fatty acids. Remember the fatty acid is really one part of a tail of a lipid. But here I'm just showing one leg. This is a very simple fatty acid. It has a negative charge up here and then it's fully saturated. All single bonds I can rotate around every single bond here. And this fatty acid is not going to work at all. No effect whatsoever. This one on the other hand it's the same fatty acid but now I have six double bonds. How on earth can there be such a large difference? You should be able to know that based on what you know in this class. Take a minute and think about it and turn your back on. Are you back? This molecule has lots of freely rotating bonds so it had lots of entropy in the unbound state, right? That meaning if I'm taking this molecule and now forcing that to bind to that channel I'm going to lose a lot of entropy that I'm binding. That's going to be bad so it's not going to be a good free energy of binding. This one on the other hand has less freedom in the unbound state. So when I bind this one I might still lose entropy but I'm not going to lose as much entropy and that means that it will likely be a better binding just as the number of freely freely rotating bonds in the small drugs I spoke about in lecture 11. Samira Yasti who used to be a postdoc with us has taken these fatty acids and simulated them actually and they behave quite differently in membranes and in particular the polyunsaturated ones they're called PUFAS polyunsaturated fatty acid. They are very free to move in this membrane and what she did is that she took a bottle or something 64 I think and just let them diffuse around a voltage sensor and it turns out that they spontaneously diffuse to and find these charges which is reasonable because these charges are positive while the polyunsaturated fatty acid has negative charges on top. Not only can we see that they diffuse to and bind to the right residues on that S4 helix if you now take those residues and go into the lab. Well the first thing we see is that if we're adding this polyunsaturated fatty acid in the lab the channel opens earlier meaning and that's what you see in the top left plot here that I don't need to change the voltage over the membrane as much to make them open and that's exactly what we wanted to achieve right the protein will open earlier but we're not 100% certain that they're binding in the right place. Do they really have the mechanism I think they have? Well what we hoped for is that they would bind to these residues and essentially place a negative charge on top of those residues right? And if you have a bunch of positive residues down here and I would like them to move up placing a negative charge here is certainly going to create a bit of attraction. The way to test that is to now try to mutate away those residues where we think it's binding and then see if we abolish the effect and that did indeed happen. So with a combination of molecular dynamics and lab experiments we can then show that we have a reasonable hypothesis how it binds that is supported by molecular models if we take the residues that these models predict they would be in touch with the effect disappears and that starts to make a very strong story that we really understand this. The problem with this is that it's not really healthy to eat copious amounts of fat all the time so what we would like to do is create smaller molecules that have similar effects. Frédéric and Sara are actually working on that and they have some very promising results but in the meantime it is actually possible to abolish some of the effects in this type of epilepsy simply by eating lots of polyunsaturated fatty acids. This is remarkably cool because lipids in contrast to proteins they're not synthesized from DNA or anything right these lipids they come from the stuff we eat in particularly the fatty acids in the stuff we eat so by changing my diet I can literally change the composition of the cell membranes in all my cells and in this case we can use that to influence how the channels in our nervous system behave so be careful what you eat you literally are what you eat.