 The KCSA channel, as I mentioned, is a bacterial channel. It turns out that it's opened or closed by pH. Why is not exception important for us? But this is very common for bacteria. They're simple organisms. They don't have a nervous system and they usually have small proteins optimized for being very efficient in terms of energy turnover. Interestingly enough, we have relatives of these proteins in humans, in particular this one. This is a so-called KV channel. I'll have to draw that up here. KV. K is because it's conducting potassium ions and V is that it's voltage gated, meaning that when the voltage across the bilayer changes, we will open or close this channel. You might be able to see the similarity between the central part of the KV channel here and the whole KCSA channel. That's not a coincidence. This, too, is a tetrameric factor. The entire orange part here is connected to the red part here, and then these four parts are stitched together so that they form, on the one hand, a central ion conducting pore here, and then these extra components that are going to be responsible for the voltage sensitivity. So how do we create something that responds to voltage? Well, this is the beauty of physics. There is pretty much only one simple way to do that. We need a charge. Why? Well, if I have an electric field that is a gradient of electrostatic potential, right? If I put a charge in that field, the charge will feel a force, which is either in the direction of the field or against the field, depending on whether it's positive or negative. So somehow we're going to need a charge in this protein. This is a side view of those four units I showed up there. I'll show it to you from the top, too. You see the blue helix here, and it's a blue helix in the rear here. The blue parts of this helix are arginine side chains, and these arginines are, in fact, charged. And now you might complain then, say, that I said that charges can never exist on the inside of the membrane. Yes, I know that's true, and we were all very, we were surprised when we saw this. In fact, some of Gunnar von Heiners and other people studies, they were studying the effective cost of inserting helices in membranes. And of course, we expect all membrane proteins to have helices that are favorable to insert, but there were a handful of these that were exceptions to the pattern. They were not predicted to be membrane helices. And this helix, which is particularly called S4, segment 4, the fourth helix in the sensor, is one of them. It doesn't contain one charge. It doesn't contain two charges. It doesn't contain three, but at least four charges. So that would be four times 20 kilocalories, 80 kilocalories. That would never happen. There is a long story behind this that I won't be able to tell you, but over the years we've learned that this is, in fact, a membrane protein helix, and it's stabilized by the neighboring helix. The other point is that this is not turning its charges against me, if I'm the membrane here, but if you look up at the structure here, that will turn the charges against other parts of the protein. Not just that. These can also be stabilized by the lipid head groups here. But if I now have these charged residues, if I'm changing the potential, there will be a force on this acting either upwards or downwards. And this is how the channel undergoes its cycle. When I'm changing, so normally I would have minus 100 millivolts, and at minus 100 millivolts, I'm going to move this helix down. But when the potential across the cell changes, it's so-called depolarized, that will cause the helix to move up. When this helix moves up, there is a small linker to the central pore here. That linker will pull all those four segments in the middle, and then we will open up the middle part of the protein and let through ions. When those ions are let through, that will change the potential across the bilir. And in fact, I'm now going to neutralize the cell a little bit further. This leads to a chain effect, that if I draw a nervous cell here, normally I have plus, plus, plus, plus, plus, and then minus, minus, minus on the inside. But something happens here, that I'm getting a neutralization, so that suddenly there is zero potential here, that is going to cause additional channels to react. And then I get a change, so there has been some positive ions flowing in. Now I have a net neutral charge here. Then more channels will open. Then the potential will have changed. Then more channels will open. The potential will have changed. More channels will open. The potential will have changed. Do you see what's happening? This is in fact how the nerve signal is conducted inside nervous cells. It goes exceptionally fast. Just think of moving your finger or sensing the heat on the stove or something. So within a few milliseconds or so, this signal will go from my brain down to my finger to a chain reaction of billions of these voltage gates of channels. Isn't it amazing? It's so amazing that can't realistically be true. There is no way the channels can open this way, can they? In fact, through computer simulation now, we know that they can. And I'll show you. This would have been science fiction when I was a student. But let's take a protein, just showing one subunit here, and then we've just depolarized the membrane. No, sorry, I repolarized it. I've added it. So what's now going to happen is that you're going to see this helix moving, the red one, and that will pull along this orange pour. Do you see it happening? Not. Let's do something else. Let me show you all four subunits from the top, because that will show you the actual pour closing. So here we are moving very quickly. In microseconds here, we're going to have hundreds of microseconds. The pour was initially open, but as these helices are relaxing down, well, we're pulling them down with the potential, do you see here that the central pour of the protein is gradually closing? So this is a large and very expensive simulation when you're showing the protein here, but in addition to the protein, we have a full lipid bilayer, you have water in you of everything, and the potential we're simply applying by adding an electric field in the simulation cell. And this was one of the first ever examples showing a complete simulation of a conformational change in a protein. And that shows that what I told you on the previous slide wasn't science fiction. This is indeed how it happens, and it happens because this helix is feeling a force due to its charges that is pulling on this linker, that is in this case causing the central pour to relax. In the opposite direction, we would be pulling on the central pour and pulling it open instead. Very cool, right?