Exploring the World of Protein Molecules

I would like to tell you about the protein molecule. Protein molecules are a class of chemicals in your body that do everything that run your system, your body, and other living systems. They make you walk and talk and think. They run your immune system. They run your brain. They run your heart. They digest your food for you. Now, protein molecules are the subject of Biology 101 courses everywhere. I am not going to tell you how to make protein molecules. I am going to tell you how to make protein molecules. I am going to tell you how to make protein molecules. tell you about that basic subject, but rather instead what I'm going to tell you about is two fairly new and very important developments focused on protein physics and protein engineering and the exciting implications they have for potential new technologies. First thing I want to do is just introduce you or remind you, for those of you who have seen this before, what a protein molecule is. They are very small. You have billions of trillions. of them inside your body. And a metaphor you could say, if you could scale up a protein molecule to the size of a penny, the number of protein molecules you have in your body is the same as the number of pennies that would fill the Pacific Ocean. You have lots of them. They're extremely small. Now, on the other hand, having said this, let me say also that protein molecules among molecules are very large and big and complex. and this is a picture of one. This is a picture of a relatively small protein molecule. The beads that you see on this diagram are atoms, and the little lines connecting them are chemical bonds. And a key feature of protein molecules is that they are long and stringy, and they are made of... I've colored here. These are false colors. Chemicals don't have color. I've colored these beads along the chain. They look like beads on a necklace. The beads themselves are like beads on a necklace. are the components of protein molecules and they're called amino acids. Amino acids are very simple chemicals. You can go down to your drugstore, you buy powders, they're a couple of bucks, they go by names like valine and isoleucine and glutamine and phenylalanine and things like that. Those are the component pieces. This is a picture of showing you the string. Sorry. There we go. This is just a schematic representation that strips out some of the amino acids so that you can see. two things. One is the basic long stringy character of a protein molecule and secondly what an amino acid looks like along the chain. I've stripped out all the rest. Now the first major development I want to tell you about is is a thing called the protein folding problem and the protein folding code. This has been considered one of the grandest challenge problems for the last 50 years in biochemistry. The protein molecule has a code, and the question is how to break it. And what I want to report to you is that a community of biophysicists has come now very close, has solved many of these problems, both high-level problems and the detailed problems, and we can now compute the structures of proteins in computers. Here's what we've done. Here's what the code is. Think about this necklace, if you like, as being made up of pearls that have 20 different colors. The 20 different colors represent the 20 different types of amino acids, so they represent the different chemical types. I'm just using a metaphor here. Suppose you could string those pearls together in any order you wanted to, red, green, blue, blue, pink, and so forth. It turns out the way you string those pearls together, the amino acid sequence, determines how this long stringy molecule crunches down into a crumpled version, which we call the shape. Now one string of colors, blue, blue, pink, will crunch into one shape and that shape may become a part of your muscle. A different string of pearl colors will crunch down into a different shape and that will perform, that will be, let's say, an antibody protein in your body. So this... This, the code, is how the string of amino acids encodes what the shape is. That's the protein folding problem. I want to describe some advances in that area first. And then the second part of the problem is once you know the shape of the protein, how can you tell what it does and how it works? These are the two key components for understanding the functioning in your body of protein molecules. Thank you. Now I'm going to show you the folding. ...problem and what we're looking to try to do. This is a protein that's all stretched out. You see four red-colored amino acids here. And the basic idea is this is a chain that needs to find its shape. And we know that these four red beads, we know after the fact that these four red beads need to find each other. It's very much like you walking through a crowd of people trying to find your close friends. It's a fairly random process, but sooner or later you can sometimes do it. Those red beads need to find each other. This is called folding. And if you look at the blue strands, what they need to do is they need to line up like train tracks. And what the gold part needs to do is coil up like a helix. And this is showing you the folding process. And one thing you'll notice is that these pieces form and they do it systematically. The other thing you will notice, so this is the final shape, and this is the shape that your protein has when it's in your body. This is the shape it needs to function. But the other thing you notice about this movie is it's very jiggly. Why is that? It's because protein molecules are so small that they get banged around by water molecules. Think about riding a bicycle in a windstorm. You're trying to get somewhere, but you keep getting blown around. And that's how protein molecules have to function too. They have to deal with these little microscopic windstorms. So this is the shape of a folded protein. The folding problem and the folding code is the business about if I knew what the sequence of amino acids is, how do I figure out what the structure is? Now this next picture is showing you a more realistic, bigger protein molecule. Most protein molecules are bigger than the one I just showed you. They often look something like this. And now I want to switch from talking about the folding problem per se to talking about mechanisms and functions. And the case I want to make for you is that proteins are machines. You have 20,000 odd different types of machines in your body and then other kinds of living organisms have other kinds of protein machines. There's tens of thousands to hundreds of thousands of different machines. And the first case I want to make for you is that these are real machines. That's not a metaphor. They use energy, they spin around, they pump, they act to cause force and motion. This is just a side view, a static view of a thing that is a protein motor. That light gray at the top is your cell membrane. Above it is the outside of the cell. Below it is the inside of the cell. And this is just showing you a static picture, and now what I'm going to do is to show you a dynamical movie of how this machine actually works. This is a picture of that, this is a movie of that machine, and what you can see is it pumps acids. Those are the little cubicle things. in and out of your cell so that it keeps the pH balance in your cell and the things down at the bottom little cards going in and out that's where the energy comes and goes and what you can see is a ribbon diagram so that shows you this nature of the protein molecule and a critical point that I want to make about that movie and about how proteins function in general is they function by shape and by shape changes and you could see that protein molecule going back and forth as different chemicals come and go. Shape is the critical thing here. Next I want to show you another type of rotary motor. It's one that does not pump acids in and out of cells, but rather it actually creates force. If you're a bacterial cell, you need to propel yourself around in water to find food. What you need is something like the propeller on the back of a boat. But life doesn't have propellers for various reasons. Instead, what it does is it has long tails called flagella. And so now I'm going to show you a movie of a rotary motor that runs the tails on bacteria. Here you see it. Those are the tails. Now you're zooming in, and you're going to see the rotary motor in kind of a cartoony-like fashion. This, too, is a real protein, and it uses energy, and it creates motion. That's rotary proteins. Those are a couple of many rotary proteins. Now I'm going to show you another kind of protein. This is a motor that slides back and forth. It walks like two feet. It's like a drunken sailor. Some of you who are old enough may remember those old cartoons about keep on trucking where you walk like this. That's what these things do. The ATP and the ADP at the bottom where the feet are, incidentally they're called heads, but where the feet are, that's where the energy comes in. And the motion happens in a general direction, but again it's battered around by the water. And these kinds of motors are used in your muscle. So every time you... do anything. These are sliding motions that are happening at the microscopic scale that cause that to happen. One of the great things about protein motors compared to real world, big world motors if you like, is they don't make noise. And the last example I want to show you of a protein mechanism is this. Some proteins are valves and pumps. This is a case where this one too sits in a membrane and it controls water flow in and out. Other such valves and pumps control lots of other things that go in and out of your muscles, and this is how your nervous system works, for example. If these kinds of proteins go bad, you get things like cystic fibrosis, for example. I've just shown you a few examples of tens of thousands of protein machines, but the case I want to make for you is just to convince you they are real machines, just at the super-microscopic level. Now, one thing that's really interesting to... those of us who are in this community about the mechanism of these machines is they don't work anything at all like big world machines. Let me tell you about two big world machines. One is electric motors and the other is gasoline engines or internal combustion engines. We don't work by the principle of electric motors. Electric motors, you plug something in or you hook something up to a battery and then the electricity causes an electromagnet to turn that into force. We don't have electromagnets. No living system has electromagnets. We don't plug in. We don't use batteries, except Iron Man maybe. Gasoline engines, they work on a different principle too. What they do is they take gasoline and they explode it and vaporize it and then turning the liquid into a vapor applies pressure and that's how it pushes on pistons and makes your car go. We don't have explosions either. We use a third principle. And the potential for this third principle is that we know it works because life has been around for three billion years and so we've seen lots of machines that work this way and yet we're not using it for any of our big world machines. So there's a lot of technological promise here that we could be using it for our big world machines. And the principle that I want to show you is just motion. It's just the motion, the protein is a blue blob here. The red thing is something that it's grabbing onto. This is part of its action. So proteins often bite onto smaller chemicals. This is how they often function. And now what happens is I'm going to show you that another molecule can come in and bind to the protein. Another chemical can come in and bind to the protein. And when it does, the shape changes, and then that causes the other molecule to unbind. This is the basic principle behind protein mechanisms in general. This is also the basic principle behind how pharmaceutical companies design drugs. Most drugs are designed against proteins. Let's say that blue thing is a protein inside a germ, a bad guy organism, some bacterium, something you want to kill if you're a pharmaceutical company. What you do is you then make a small chemical, the yellow thing, that goes in and binds to the bad guy protein. And so the bad guy protein drops whatever it was supposed to hold on to and that kills the bad guy cell. This change of shape is the critical principle that works in biology. We know a little bit about it. There still remains to be a huge amount of science done. So obviously one thing that proteins are important for is for understanding health and for curing disease. But the other thing that I want to make a case for you about ...is the prospect of us scaling up small world machines like proteins to the big world. The big world machines are a really important part of our quality of life and our commerce. It turns out that if you look from the poorest countries to the richest countries, there's about a 50-fold difference in income per person. There's also a 50-fold difference in energy utilization and machine usage. It turns out that electric motors use half of the world's electricity. Gasoline engines use a third of the world's total energy supply. Machines in general are very important for commerce. Protein molecules are important too. There's a half a trillion big world machines out there in the world right now. You have more machines in the tip of your little finger than there are total big world machines out there. And one other measure of importance is, think about whether you'd rather have your car motor be dead, or whether you'd rather have cystic fibrosis or Parkinson's. Alzheimer's where your proteins are dead. There's huge prospects for scaling these up, for solving problems having to do with water supply, health, energy, solar energy conversion, human transportation, information. We see it on the micro scale. we should be able to make it work on the macro scale. How do we know we can do that? Here's an example. We've been using human transportation for more than 100 years, or in fact much longer than that, that's based on... scaling up small world machines and that is what you do is you sit on the back of another animal like a horse or a camel or a donkey or a mule and you ride them. However in the future the promise is not having to shovel manure anymore we ought to be able to do this a lot smarter. Hopefully this is a future that you or your kids will see. The great thing about this field is that it's one of the rare cases in history. where you can already see how a technology works in great detail before you've even developed it. We see it work on the small scale. It's just a matter of can we scale it up. We just need to learn the principles. We just need to figure out how to harness it. And conceivably, it's a future you will see and we will all see if that happens. Thanks for listening.

They run your brain. They run your heart. They digest your food for you. Now, protein molecules are the subject of Biology 101 courses everywhere.

I am not going to tell you how to make protein molecules. I am going to tell you how to make protein molecules. I am going to tell you how to make protein molecules. tell you about that basic subject, but rather instead what I'm going to tell you about is two fairly new and very important developments focused on protein physics and protein engineering and the exciting implications they have for potential new technologies.

First thing I want to do is just introduce you or remind you, for those of you who have seen this before, what a protein molecule is. They are very small. You have billions of trillions.

of them inside your body. And a metaphor you could say, if you could scale up a protein molecule to the size of a penny, the number of protein molecules you have in your body is the same as the number of pennies that would fill the Pacific Ocean. You have lots of them. They're extremely small.

Now, on the other hand, having said this, let me say also that protein molecules among molecules are very large and big and complex. and this is a picture of one. This is a picture of a relatively small protein molecule.

The beads that you see on this diagram are atoms, and the little lines connecting them are chemical bonds. And a key feature of protein molecules is that they are long and stringy, and they are made of... I've colored here. These are false colors.

Chemicals don't have color. I've colored these beads along the chain. They look like beads on a necklace. The beads themselves are like beads on a necklace.

are the components of protein molecules and they're called amino acids. Amino acids are very simple chemicals. You can go down to your drugstore, you buy powders, they're a couple of bucks, they go by names like valine and isoleucine and glutamine and phenylalanine and things like that. Those are the component pieces. This is a picture of showing you the string.

Sorry. There we go. This is just a schematic representation that strips out some of the amino acids so that you can see. two things.

One is the basic long stringy character of a protein molecule and secondly what an amino acid looks like along the chain. I've stripped out all the rest. Now the first major development I want to tell you about is is a thing called the protein folding problem and the protein folding code. This has been considered one of the grandest challenge problems for the last 50 years in biochemistry. The protein molecule has a code, and the question is how to break it.

And what I want to report to you is that a community of biophysicists has come now very close, has solved many of these problems, both high-level problems and the detailed problems, and we can now compute the structures of proteins in computers. Here's what we've done. Here's what the code is. Think about this necklace, if you like, as being made up of pearls that have 20 different colors. The 20 different colors represent the 20 different types of amino acids, so they represent the different chemical types.

I'm just using a metaphor here. Suppose you could string those pearls together in any order you wanted to, red, green, blue, blue, pink, and so forth. It turns out the way you string those pearls together, the amino acid sequence, determines how this long stringy molecule crunches down into a crumpled version, which we call the shape. Now one string of colors, blue, blue, pink, will crunch into one shape and that shape may become a part of your muscle.

A different string of pearl colors will crunch down into a different shape and that will perform, that will be, let's say, an antibody protein in your body. So this... This, the code, is how the string of amino acids encodes what the shape is. That's the protein folding problem. I want to describe some advances in that area first.

And then the second part of the problem is once you know the shape of the protein, how can you tell what it does and how it works? These are the two key components for understanding the functioning in your body of protein molecules. Thank you.

Now I'm going to show you the folding. ...problem and what we're looking to try to do. This is a protein that's all stretched out.

You see four red-colored amino acids here. And the basic idea is this is a chain that needs to find its shape. And we know that these four red beads, we know after the fact that these four red beads need to find each other. It's very much like you walking through a crowd of people trying to find your close friends.

It's a fairly random process, but sooner or later you can sometimes do it. Those red beads need to find each other. This is called folding. And if you look at the blue strands, what they need to do is they need to line up like train tracks.

And what the gold part needs to do is coil up like a helix. And this is showing you the folding process. And one thing you'll notice is that these pieces form and they do it systematically.

The other thing you will notice, so this is the final shape, and this is the shape that your protein has when it's in your body. This is the shape it needs to function. But the other thing you notice about this movie is it's very jiggly. Why is that?

It's because protein molecules are so small that they get banged around by water molecules. Think about riding a bicycle in a windstorm. You're trying to get somewhere, but you keep getting blown around.

And that's how protein molecules have to function too. They have to deal with these little microscopic windstorms. So this is the shape of a folded protein.

The folding problem and the folding code is the business about if I knew what the sequence of amino acids is, how do I figure out what the structure is? Now this next picture is showing you a more realistic, bigger protein molecule. Most protein molecules are bigger than the one I just showed you.

They often look something like this. And now I want to switch from talking about the folding problem per se to talking about mechanisms and functions. And the case I want to make for you is that proteins are machines. You have 20,000 odd different types of machines in your body and then other kinds of living organisms have other kinds of protein machines.

There's tens of thousands to hundreds of thousands of different machines. And the first case I want to make for you is that these are real machines. That's not a metaphor.

They use energy, they spin around, they pump, they act to cause force and motion. This is just a side view, a static view of a thing that is a protein motor. That light gray at the top is your cell membrane. Above it is the outside of the cell. Below it is the inside of the cell.

And this is just showing you a static picture, and now what I'm going to do is to show you a dynamical movie of how this machine actually works. This is a picture of that, this is a movie of that machine, and what you can see is it pumps acids. Those are the little cubicle things.

in and out of your cell so that it keeps the pH balance in your cell and the things down at the bottom little cards going in and out that's where the energy comes and goes and what you can see is a ribbon diagram so that shows you this nature of the protein molecule and a critical point that I want to make about that movie and about how proteins function in general is they function by shape and by shape changes and you could see that protein molecule going back and forth as different chemicals come and go. Shape is the critical thing here. Next I want to show you another type of rotary motor. It's one that does not pump acids in and out of cells, but rather it actually creates force. If you're a bacterial cell, you need to propel yourself around in water to find food.

What you need is something like the propeller on the back of a boat. But life doesn't have propellers for various reasons. Instead, what it does is it has long tails called flagella. And so now I'm going to show you a movie of a rotary motor that runs the tails on bacteria. Here you see it.

Those are the tails. Now you're zooming in, and you're going to see the rotary motor in kind of a cartoony-like fashion. This, too, is a real protein, and it uses energy, and it creates motion.

That's rotary proteins. Those are a couple of many rotary proteins. Now I'm going to show you another kind of protein.

This is a motor that slides back and forth. It walks like two feet. It's like a drunken sailor. Some of you who are old enough may remember those old cartoons about keep on trucking where you walk like this. That's what these things do.

The ATP and the ADP at the bottom where the feet are, incidentally they're called heads, but where the feet are, that's where the energy comes in. And the motion happens in a general direction, but again it's battered around by the water. And these kinds of motors are used in your muscle. So every time you...

do anything. These are sliding motions that are happening at the microscopic scale that cause that to happen. One of the great things about protein motors compared to real world, big world motors if you like, is they don't make noise. And the last example I want to show you of a protein mechanism is this. Some proteins are valves and pumps.

This is a case where this one too sits in a membrane and it controls water flow in and out. Other such valves and pumps control lots of other things that go in and out of your muscles, and this is how your nervous system works, for example. If these kinds of proteins go bad, you get things like cystic fibrosis, for example. I've just shown you a few examples of tens of thousands of protein machines, but the case I want to make for you is just to convince you they are real machines, just at the super-microscopic level. Now, one thing that's really interesting to...

those of us who are in this community about the mechanism of these machines is they don't work anything at all like big world machines. Let me tell you about two big world machines. One is electric motors and the other is gasoline engines or internal combustion engines. We don't work by the principle of electric motors. Electric motors, you plug something in or you hook something up to a battery and then the electricity causes an electromagnet to turn that into force.

We don't have electromagnets. No living system has electromagnets. We don't plug in.

We don't use batteries, except Iron Man maybe. Gasoline engines, they work on a different principle too. What they do is they take gasoline and they explode it and vaporize it and then turning the liquid into a vapor applies pressure and that's how it pushes on pistons and makes your car go. We don't have explosions either. We use a third principle.

And the potential for this third principle is that we know it works because life has been around for three billion years and so we've seen lots of machines that work this way and yet we're not using it for any of our big world machines. So there's a lot of technological promise here that we could be using it for our big world machines. And the principle that I want to show you is just motion. It's just the motion, the protein is a blue blob here.

The red thing is something that it's grabbing onto. This is part of its action. So proteins often bite onto smaller chemicals. This is how they often function. And now what happens is I'm going to show you that another molecule can come in and bind to the protein.

Another chemical can come in and bind to the protein. And when it does, the shape changes, and then that causes the other molecule to unbind. This is the basic principle behind protein mechanisms in general.

This is also the basic principle behind how pharmaceutical companies design drugs. Most drugs are designed against proteins. Let's say that blue thing is a protein inside a germ, a bad guy organism, some bacterium, something you want to kill if you're a pharmaceutical company.

What you do is you then make a small chemical, the yellow thing, that goes in and binds to the bad guy protein. And so the bad guy protein drops whatever it was supposed to hold on to and that kills the bad guy cell. This change of shape is the critical principle that works in biology.

We know a little bit about it. There still remains to be a huge amount of science done. So obviously one thing that proteins are important for is for understanding health and for curing disease. But the other thing that I want to make a case for you about ...is the prospect of us scaling up small world machines like proteins to the big world. The big world machines are a really important part of our quality of life and our commerce.

It turns out that if you look from the poorest countries to the richest countries, there's about a 50-fold difference in income per person. There's also a 50-fold difference in energy utilization and machine usage. It turns out that electric motors use half of the world's electricity. Gasoline engines use a third of the world's total energy supply.

Machines in general are very important for commerce. Protein molecules are important too. There's a half a trillion big world machines out there in the world right now.

You have more machines in the tip of your little finger than there are total big world machines out there. And one other measure of importance is, think about whether you'd rather have your car motor be dead, or whether you'd rather have cystic fibrosis or Parkinson's. Alzheimer's where your proteins are dead. There's huge prospects for scaling these up, for solving problems having to do with water supply, health, energy, solar energy conversion, human transportation, information. We see it on the micro scale.

we should be able to make it work on the macro scale. How do we know we can do that? Here's an example.

We've been using human transportation for more than 100 years, or in fact much longer than that, that's based on... scaling up small world machines and that is what you do is you sit on the back of another animal like a horse or a camel or a donkey or a mule and you ride them. However in the future the promise is not having to shovel manure anymore we ought to be able to do this a lot smarter.

Hopefully this is a future that you or your kids will see. The great thing about this field is that it's one of the rare cases in history. where you can already see how a technology works in great detail before you've even developed it.

We see it work on the small scale. It's just a matter of can we scale it up. We just need to learn the principles. We just need to figure out how to harness it.

And conceivably, it's a future you will see and we will all see if that happens. Thanks for listening.

Transcript for:Exploring the World of Protein Molecules

Transcript for:
Exploring the World of Protein Molecules