 I want to show you two slightly more modern examples where we're using simulations not to specifically design a drug but to understand processes of more complicated modulation of how ion channels in particular work. Remember when I spoke about anesthesia and how important that process was and also that it's quite complicated to understand. It's not just limited to anesthetics but a wide range of drugs that we use and abuse and have done so for millennia. Alcohol is possibly the oldest drug known to mankind and all these act on the so-called ligand-gated ion channel in our synapses. These channels as I mentioned are large and complicated. They have an extracellular domain and a transmembrane domain with the drugs in particular binding in the transmembrane domain. A fascinating aspect of these drugs that we hardly understand is that they appear to almost have separate on and off buttons and that's also not just different molecules but remember if you take one glass of wine you might get happy if you take ten you're going to get tired. So it appears to even depend on the dose of these channels. Yuhuan Chuang and Reba Howard in my team they worked very close with Ryan Hipps to understand some of these receptors in particular one called the Gamma Aminobutyric Acid which is central in anesthesia. So the GABA receptor binds a certain small molecule that I showed you yesterday in terms of the drugs. The volume or diatsopam molecule. This molecule is a sedative. It's very strong so there's no coincidence that it's acting on these receptors but until recently we didn't know exactly what happened. What they were able to show using a combination of cryo-electromicroscopy and molecular simulations is that the diatsopam molecule goes into the membrane part it binds between the subunits of this channel and it kind of tightens up the entire structure. It makes the structure more rigid and changes the dynamics in the entire transmembrane domain. You can literally see this here right on the right. This is directly going to create the effect on your nervous system that gives us sedative feeling. The problem is that you can also overdose on this drug and if you overdose on diatsopam and come into the emergency room they're likely going to give you flumazenil which is a small antidote kind of like drug. We don't really know how flumazenil works either but the fascinating part, this drug has the opposite effect of diatsopam. Do you remember these agonists and inverse agonists that I talked about in the biophematics lecture? So here Yukván was able to show how flumazenil bound to the GABA receptor indeed appears to have the opposite effect of dynamics and in particular if I have flumazenil bound we're not going to get this effect if I also bind GABA. So flumazenil kind of displaces GABA, creates the opposite effect which is of course why it effectively works as an antidote to relieve the effect of GABA and you're no longer going to die from the overdose. There is a wealth of information remaining here but here you can see that I'm not just, I am adding small molecules inside that I'm binding but now I'm adding molecules that don't necessarily create the effect themselves like the agonists or inverse agonists but these are allosteric modulators. They're secondary modulators kind of similar to hemoglobin effect and these modulators can then either be positive or negative allosteric modulators so either strengthen or dampen the primary effect. You could spend a life in this business, it's amazing but in the interest of time I'll move on to the next example.