 So this far things have been a bit abstract before we go on to a cookbook and take you through a flow chart of the simulation Let me show you the type of things we can analyze in this This is a simple voltage sensor in a voltage gated ion channel that I already spoke a bit about in the first lecture It's been possible to use simulations to simulate how this fourth helix s4 moves up and down amazing work This is a protein that several people in my group have worked with it's a large ligand gated ion channel embedded in a complete membrane of lipids and then Full water around it maybe 200 250,000 atoms a very large even by today's standards The type of problems you can approach both we and others have started for instance What's happening if one of those voltage sensors is binding a toxin? We know that some of these toxins tend to open voltage channels while others close voltage channels And we can use simulations to understand the difference here either for different toxins or for different channels Again in the experiment we can see that they open or close the channel But the experiment won't give us the molecular detail of how it happens and combined They will both explain why are the interactors happening? Where are the interactions happening and then correlate that to the actual opening or closing that we see in the experiment? But we might actually not see the full opening in the simulation This is another example when you're calculating the free energy of binding a small compound in a protein But in this particular case, I would like to also know what if I now change one residue to my protein Say from a felon alanine to an alanine that is common saying a virus So if you have a drug that we know has an effect against the virus But there is now a mutation in the virus will this drug still work will it still bind and a computer simulation can calculate that? We could even imagine screening through all positions even before we have these virus sequences and everything Which in theory can help us speed up drug development free energy calculates are used a lot in drug development And I will talk about that more later in this class What all these things have in common is that we would like to study large systems And we would like to study long time scales hundreds of thousands of atoms and several microseconds Today, I would say that the state of the art is somewhere around a microsecond per day at least on normal computers There are a ton of motions. We can understand here. This might even be a bit conservative There are quite a lot of biology people are publishing on this, but we can thoroughly Characterize motions at least If you have access to a special purpose computer such as that the show and the machine You might be able to get one order of magnitude further And maybe you can get there with the largest coming supercomputers That's the way they were able to simulate the full opening of the activation of this vaulted sensor in a protein that I showed you in the first lecture and at least we can definitely Interpret experiments and show the same type of biological process in the simulation as we had in the experiments again My formulation here might be a bit conservative And I bet given how this is developing and that we're having better and better algorithms and faster computers Even if the individual simulations won't reach milliseconds We will gradually be able to study processes by collecting in the ballpark of a hundred microseconds of simulation data per day And we're gradually going to head into the realm where maybe Replacing experiment is the wrong way of placing it But rather than we can study the same process in the computer as you start in the experiment But where the experiment provides an absolute yes or no answer if it happens The computer will provide the mechanistic detail about the molecules why it happens And maybe at some point in the future before I retire we can get up to a millisecond per day That would be awesome, but I wouldn't bet on it