 Welcome to the class on molecular biophysics. I'm Erik Lindahl and I'm going to be your teacher for the next 12 or 13 lectures. Great to have you here, even though it's only virtually. What I'm going to do with the class is that although there are 13 so-called lectures, each of these lectures is going to be split in between 10 and 20 small concepts where I try to divide things up so that you can rehash a concept until you feel you understand it. If you want the traditional lecture, just view the entire playlist and then go back and repeat each concept until you feel that you master it. Today is a bit special, though, since it's the first lecture and that means that I'm going to start with a slightly longer introductory concept to give you a bit of an overview of what we're going to be looking at in this class and the type of problems we're interested in, both in biophysics in general and in molecular biophysics in particular. So, join me. The first things I'm going to tell you is that biophysics is everywhere around us. I'm sure you've all seen things like an insect being able to walk on water. There's an amazing amount of biology and evolution in this problem, but at the heart of it, this is a physical concept that the surface tension of the water, i.e. the special properties of water, makes it possible to do something biologically, in this case for a very lightweight insect to walk on it. You can have another challenge. Imagine something highly complicated compared to an insect, such as a bird flying over billions of years of evolution. Birds have evolved into being able to flap their wings at the very right point in time to maximize the amount of lift they get relative to the energy they're putting into this. Of course, the bird doesn't know how to do this. It's just mechanically, it does it the right way. Well, I'm not a bird, so I don't know how. But one way or another, they do manage to do it without having taken an advanced degree in physics. Of course, we can calculate this, but biology has somewhat managed to do this through billions of years of evolution. And in the muscles of this bird, we essentially have proteins. And in the brain, you have nerve cells controlling this. We're not going to be looking that much on birds in the particular class, but the concepts will keep coming back and looking at problems. Something else that we're not going to be looking at the class is, say, fish swimming in a school. There is a lot of information you can learn from fish. Sabra fish is used in almost all facilities for molecular life sciences to express proteins. But what about the particular problem of understanding why fish swim in a school? That is, many of them swim together. Well, colleagues of mine who are actually computer scientists and mechanical engineers in Switzerland, they have studied that. And by using supercomputers and fluid dynamics, we can use physics, fluid dynamics to understand that when fish swim together in a school, they actually reduce the total amount of energy needed. And by taking turns of who's swimming in front, that means that they save energy. And that is then a behavior that has been encoded and encouraged by billions of years of evolution. If we're looking at another animal, a modern animal, that is a researcher doing, say, artificial intelligence or deep learning, today we might be doing things like putting cameras and monitoring how fish are swimming. And then we might be administering different type of chemicals, drugs, and then adapting and catching patterns and see how the fish adapt to this and then draw conclusions about the behaviors. So there is a wealth of information you can do, not just on cellular biology, but even organism biology that uses modern methods founded in physics and computer science. That's not going to be this class, though. In this class, we're going to be mostly stuck in the other end. And in the other end of things, we have the molecules, and that's a world that I hope to introduce you to and that you too will see how amazing it is. So biology, in contrast to many provinces, is fascinating because we have so many scales. Looking here, we're starting from a tree where you might have scales of meters or tens of meters, even 100 meters in cases in the world. If we're zooming into that on a leaf, we might first be at centimeters. You're getting to millimeters where we're starting to see internal structures. You're eventually seeing cells below the millimeter level. And then we're starting to see organelles, parts inside cells. A tree is almost as complicated as a human cell, but they have slightly different composition of their cells. And somewhere very deep down, in this case, it's not even a microscope but a molecular model of it, we're having proteins that are at the ends that give these cells their properties and the way the tree works. So here we've probably had things spanning something like nine orders of magnitude in space, which is fairly impressive. We can choose to model this either top-down or bottom-up, depending on what we're interested in. So the top-down studies would be starting from the tree and then going down, but in particular with the advent of modern computers, we're increasingly able to study things starting from the molecules and then understanding how all of these molecules work together. Both approaches are powerful and they complement each other. We can start and make this complicated by doing it two-dimensionally too. So in this diagram on the x-axis, we have the scales, the length scales I talked about. Here we go even further because beyond the symbol three or something, you could think of humans, and in addition to one human, it would be scales of meters. You could even think of going to population dynamics. How does the population all over the world increase or adjust, for instance relative to disease or so? So that would be scales of kilometers even. But then we have corresponding scales here on the y-axis that has to do with scales in time. The fastest motions might then be something moving on nanoseconds, atoms vibrating inside proteins. We're going to spend a lot of time talking about that. But then we have cellular processes, proteins folding, maybe up to a second or so. The life spans of cells, eventually the lifespan of an individual that might be 100 years. And if we're thinking about evolutions, then we might be even talking about billions of years. So here too we have 9, 10 if not more orders of magnitudes that are spanning across both space and time, which I think is quite unique to biology, which it makes it complicated, but that's of course the fun aspect, and that's why we're doing research on it, because we don't know all these things yet. Let me take you down to the molecule level two. This is an example that we're going to get back to later on. So these are a couple of different small proteins, engines sitting in a cell membrane, and they're responsible for the energy turnover in your cells, part of it at least. So the green parts here are so-called ion channels that are fairly simple doors, windows that just open up, and when a door that fits a particular ion opens up, that type of ion will be able to flow through it. So in this case we have two different ones, one that's conducting potassium ions and another one that's conducting sodium ions. We're going to come back to what they do later on when we talk about the nervous system. These channels are fairly simple. So for something concretely to happen here, in a potassium channel for instance, you need to have an excess concentration of potassium on one side of the cellular membrane, and when this channel opens up, ions flow from the side where the concentration is higher to the side where the concentration is lower. That's a completely passive process that doesn't require energy. We're just equilibrating things. But that will of course lead to a nerve impulse. The reason we can do that though is that we're essentially using energy there, right? At some point we're going to need to charge up this energy. And that's done by the simple protein in the middle, which is not a channel, it's a transporter. It's a transporter that is moving both potassium and sodium ions at the same time actually against the concentration gradient. So this one is moving potassium ions from the side where the potassium concentration is low to the side where the potassium concentration is high. That's a process that won't happen spontaneously. And since it won't happen spontaneously, we're going to need to use energy, expand energy to make that happen. This is a very well-known protein and we even have structures of this. Jen's school got the Nobel Prize for this in 1997, I think it was. We even have a complete structure of this one, but before I show you the structure of the protein, I'm going to show you the structure of this. This is the energy. The ATP, adenosine triphosphate. That's typically how we store chemical energy for fast turnover inside the cells. There are some glycogen depots and everything where we store long-term energy. But by taking this molecule and tearing off one of these phosphate groups, we can release some of this energy. And then we turn the molecule into an ADP, adenosine diphosphate. The molecule I talked about, which is the sodium potassium ATPase on the previous slide, that one is using this process and using the energy stored in ATP to transport these ions across the gradient. And oh my God, is it using this a lot? Our bodies are turning over something in the ballpark of 70 kilos of ATP per day. It's of course reusing the molecules. That's why you don't have to eat 70 kilos of food. But there is an insane amount of energy being turned over in this and generated all the time. We'll get back to that. This is another important membrane protein, GPCR, G protein coupled receptor that is responsible for lots of the signaling in our bodies. So we're having different small compounds, drugs attaching here. The entire protein goes through a protein earthquake and this leads to a signal being transmitted to the inside of the cell where we have this G protein connected. This was one of the major advances in pharmaceutical structure determination when Ray Stevens and some colleagues were able to determine the first structures of them. The way we determine those structures is typically done with synchrotron light radiation, x-ray crystallography, that I'm also going to have a chance to talk to you a little bit about today. There are other ways we could do it though. Traditionally we would do this in the experiment but given the speed of computers and models under some conditions we can actually take this into a very fast computer and let the computer solve new terms equations of motions. In this case we're seeing a small ligand binding in a computer and what the computer is then doing on a femtosecond scale we're checking how things evolved and then you're going to see that the protein here actually changes its conformation and eventually there's a large conformational shift and in parallel with these studies we've actually been able to show that that does indeed correspond to the structure of the bound GPCR. So the computer here has been able to not just determine the right structure but actually tell us what's happening in the process which is an amazing new way that we can occasionally use to gain more understanding of biology. Now instead of doing that in the lab you're doing that with custom very large computers. There is a race in there both the US, Europe and China are investing tons of money in so-called excess scale computing that an insane amount of computational operations per second many of them are used for biology many of them are even used for our program, GROMACS and that you're going to be using a bit in labs later in the class. The question though, this is just a model and it's important not to fall in love with your model that's a theme that I'm going to repeat during this class and we need to check is that a correct prediction or an incorrect prediction and the reason I'm showing this one to you is of course that it turned out to be an amazing prediction. Sadly this was not me but the David Shaw group doing this. What you see here in purple the purple molecule here is the one that the computer predicted and the gray molecule is the post that was then later and confirmed in the lab and you see they superimposed perfectly. It's so good that you couldn't tell which one is which this is beyond the resolution of the experimental result. The reason why both academia and companies are investing so much money in this is that this is the way we discover new drugs. We start, well most of them we need to start with the structure of a protein and then we're identifying a small drug that combined and changed the behavior of this protein and just for the GPCR molecules here you have a whole bunch of drugs that have been discovered the last few years and then made it to the market. So while we're talking about this from a research point of view, physics and understanding things, this is very directly saving human lives and improving health all over the world so it's a quite direct way of improving human conditions. Although we're mostly going to stay on the molecular level in the class, occasionally we will go a little bit beyond molecules. So beyond molecules, you're having organization inside cells. Different proteins might go to different parts and compartments of the cell, for instance the nucleus or the endoplasmic reticulum and a few other things that we'll explain later in the class. Beyond individual cells, we also have different types of cells. A heart cell is not identical to a lung cell is not identical to a brain cell is not identical to a cell in the peripheral nervous system. We will talk a little bit about that but probably limited to the part when it influences protein structure. And beyond cells, we even have different types of tissue. So again, my heart tissue has one particular type of muscles that is quite different from the muscles sitting in my biceps and triceps. Another example where this is important is when it comes to drug design because when it comes to drug design, it's not enough to get those drugs into the gPCR receptor, right? Or rather once we are at the gPCR receptor, it's fine but somehow we're going to need to get the drug to the right cell first. That's a whole research area in itself that we will only have time to browse a little bit. Occasionally we can have drugs that we can eat as a pill but sometimes we have drugs that would be digested in your stomach and then we need to find a different way to deliver them. Sometimes we do it with injections but injections are complicated because you need to go and see a doctor and you likely you want to avoid infections is also an infection risk. In some cases we would like to go across membranes. The blood-brain barrier in particular is a very complicated membrane so even if you get the drug into the blood that might not be enough because the brain is not directly communicating with most of your blood. In other cases we would like an even simpler way of administering drugs particularly if you're not gravely ill. So some of you might have taken a small skin patch. We use them for contraceptives. We use them occasionally for motion sickness and those skin patches are pretty cool because you attach them to your skin and then they're gradually releasing a low dose of a drug over 24 or 48 hours. It's great because you don't get a very large dose immediately and we continuously administer it in a very nice and smooth fashion. The reason why that doesn't work for most drugs is that our skin is meant to protect us. It's not neither water nor oil will go through the skin. So this only works for a few drugs where we've been lucky. We have two very nice people sitting in my lab actually they used to be students and postdocs here but they formed a small company called Erco and they're doing research where they're trying to use computational models like you have here where they have models of skin that they have adapted to images of skin obtaining collaborations with the Carolina Skin Institute and then they're trying to use this to optimize both delivery mechanisms and see what changes the design of the drug to make it more likely for the drug to go through skin. Very advanced research but also an example of how fundamental strong research can somehow lead to obvious commercialization opportunities. I have to confess that I have a special love in the world and this love is membrane proteins so you're going to see lots of things about membrane proteins. This is arguably the world's smallest machine. If we talk about nano technology to be a bit blunt nano technology is what people say that they're using when they have 999 nm machines. This machine is in the ballpark of 10 nm it's just for alpha helices and it's the machine that is responsible for every single heart beat in our body. When the voltage across the cell changes one of these helices moves up and that opens one of those ion channels to let potassium ions through. This is another important machine I have here. This is a ligand gated channel that occurs throughout the nervous system. If you have a glass of wine on Friday what happens to the alcohol is that the alcohol will bind to certain proteins including this one and that will change how nerve cells mediate signals from the end of one nerve cell and how it's transmitted to the next nerve cell. It's not just used for alcohol consumption but also things like anesthetics and the whole use of neuropharmacological drugs that change our nervous system work is likely going to be able to target these molecules. We already know that anesthetics do and until 10 years ago we didn't have structures of them. We couldn't really design and tailor make drugs but today we do because of research. There are many other things that I would love to tell you about. Proteins are important throughout your body. This is a small protein called hemagglutinin which this wine flew a few years ago. You might have seen the name A-H1N1. The H in that formula stands for hemagglutinin and the wine is a particular sequence of that. That is literally the small drill that the virus uses to attach itself to the cell and releases genetic material into the cell. And in similar ways there is a whole wealth of different proteins that are enzymes. If there is anything that's happening in your cell and doing something actively it's virtually guaranteed to be a small protein and we're going to be looking at a bunch of these throughout the class. Another one that I think is worth looking at when I'm recording this which is spring 2021 is this. This is a protein that has become sadly super important the last year. So this is the so-called spike protein of the coronavirus and that's what gives this crown-like shape because it's expressed all over the surface on the virus. The blue part here and the corresponding part in the other monomer there it's a so-called receptor binding domain and that's a domain that attaches itself and binds itself to these domains which are actually not part of the protein but this is the DCE2 domain that is sitting for instance on my blood cells. So this is literally the way how the coronavirus attaches itself to my cells and with them help itself release its genetic material into those cells and a whole lot both of the small compounds we tried to design to combat the virus would try to inhibit this protein and the most of the vaccine candidates work by somehow introducing just this protein not the entire virus in your cells so that your cells would then create antibodies to this protein and if you then get infected with the actual virus the antibodies will recognize the spike protein and kickstart your immune defense system to get rid of the virus. The class here is going to have a number of desired learning outcomes and I would say that there's two or possibly even three there's a bunch of fundamental knowledge I want you to understand how these biomolecules work I want you to be able to reason and explain different parts of protein structure we want you to be able to reason about dynamics we want you to be able to understand the hierarchy of molecular structure I don't think I mentioned drug design there so there are a number of fundamental basic knowledge that it's important for you to know even by heart because if you don't know it by heart you won't be able to have a brainstorm and reason about it and then there is a second part that you need an ability to synthesize information using all these knowledge there is a saying that to be successfully live research anything you need good judgment and you get good judgment from experience and you get experience from bad judgment hopefully I can help you save a little bit of time there so you don't have to gain so much experience through your own bad judgment but that you can borrow the bad judgments of previous generations of scientists but it's important to sit down and think about things and work with it to get to these second parts that enables you to be an independent strong scientist merely knowing things by heart that's important it's necessary but it's not sufficient to be able to perform research or be successful say doing drug development and industry yourself but we will start here and we will gradually get to the abilities later on in the class we are going to be speaking a lot about protein structure we're going to be speaking a lot of protein folding much of this is going to be starting from physics we're going to repeating something called sequence leads to structure leads to function the central dog molecular biology and gradually we're going to be talking a little bit about protein engineering not so much from an engineering point of view there are much better classes to do that from a practical point of view but I'm going to cover the reason why things work and we're going to cover that from a physics point of view going all the way to fundamental concepts such as free energy so the reason I love this not just this class the entire field I'm doing research in is that I find it a beautiful mix of chemistry biology and physics we are going to talk about basic concepts today a lot of it's actually going to be water which is more important than you think we're going to be speaking about DNA and RNA we're going to be speaking a little bit about protein production machinery and protein structure but that we're going to do a separate concepts