Proteins, weird blobs that do important things
Proteins are all around us, and they do amazing things to keep life going. So I’ve just released a new podcast episode of Hard Drugs with
about the wonderful world of proteins.You’ll learn about proteins in our body, why cells are like cities, what proteins are really, and how they are formed. And also about the first protein structure discovered and why it was ugly; why proteins are weird blobs, the biggest and smallest proteins, the most abundant proteins on earth, how fast proteins are, and what our favourite proteins are.
You can read the transcript below, listen on Apple, Spotify or wherever you get your podcasts, or watch on YouTube. This episode will be the first of a mini-series we’re releasing on proteins, drug development and AI. If you like it, I hope you share it with your friends, family, colleagues, and everyone you know, and subscribe!
Transcript
Saloni Dattani:
In today's episode, we're going to talk about the wonderful world of proteins.
Proteins are all around our body. We use them in our daily lives, and they do amazing things to keep us going.
Jacob Trefethen:
Protein design just won a Nobel Prize and we are going to do a mini-series of episodes here to talk about AlphaFold and other AI systems used to design proteins, whether people can increasingly design dangerous proteins, not just medicines, and whether protein design can help us get cures for some of the toughest diseases that still plague humanity.
Saloni Dattani:
But first, let's start with the basics. You might remember being in high school biology and seeing a simple diagram of a cell. It probably looked a bit like a fried egg or a sunny side up. There was the nucleus, which was a bit like the egg yolk. And then there were a few other things scattered around, like mitochondria and ribosomes, but that was a massive simplification.
In reality, cells are incredibly busy. There are billions of molecules in every cell, including loads of proteins, which have different functions. So let me just think about what are the different things that the proteins are doing? Well, there are structural proteins; they provide shape and strength to cells. There are storage proteins; they store little molecules. There are signalling proteins that help cells communicate with each other. So insulin, for example, is a hormone, a protein, and it's made in the pancreas and it tells cells to take up glucose from the bloodstream, and that lowers blood sugar after eating.
There are also transport proteins that move molecules between cells. Haemoglobin, for example, is a protein in red blood cells that binds to oxygen and carries it around in the blood. There are also enzymes — enzymes speed up chemical reactions in our body, by lowering the activation energy needed for them. There are regulatory proteins that control other proteins and pathways. And there are defence proteins that protect us from attack; so antibodies are a type of protein. Snakes and spiders have venoms, which are proteins that help them disable their threats. There are so many different types of jobs that a protein might have, and many proteins have multiple jobs at the same time.
And this means that this basic diagram view, that you might've had of a cell, was quite simple. In reality, the cell is extremely busy. It's more like a bustling city, and there are literally billions of molecules, proteins, DNA, RNA, fats, sugars, and ions — all moving around, reacting and interacting with each other.
Every part of the cell has its own job and it's a bit like different districts in the city. There's a great blog post by Niko McCarty where he describes this, and I thought it would be helpful just to have a sense of what's going on. He says, “A microbe's guts are a veritable Times Square, crowded with sugars, proteins, and water molecules that ricochet and smash into each other billions of times each second. Space is limited. A bacterium's insides are 70% water by mass; the other 30% is dominated by proteins first, followed by RNA and lipids. DNA accounts for just 1%. And all of this stuff fits inside a volume that is one quadrillionth of a litre.”
Jacob Trefethen:
That's a lot of proteins and I can't even see one of them.
Saloni Dattani:
Right? They're so small. And so if you think of this city — of each cell — the nucleus is something like the city hall, it's managing the information; it has instructions for what should happen. There are mitochondria; the power stations of the cell. There are ribosomes that construct new proteins. And then there are proteins, that are the workers and the machines of the city, but they're also the structural components and the signalling molecules and all of these things.
Jacob Trefethen:
Our body is doing so much with all of those proteins. Are proteins used outside of the body too?
Saloni Dattani:
They are! In fact, if you've done any cooking, you would know, for example, that chemical reactions change the proteins that you're cooking with. So, for example, if you cook an egg white, it becomes firm when it's cooked. That's because the heat denatures the proteins — it makes them unfold — and then it makes them coagulate into a different kind of mesh, and that makes it opaque.
There's also gluten, which is a protein that gives bread its stretchy texture — that's made of two proteins. There are also lots of proteins that are used in industry and biotechnology. If you've done your laundry recently, you might have used a detergent that was made of enzymes, and the enzymes break down stains, like fat or blood. Then there are a bunch of proteins that are used in baking and brewing and textile manufacturing. Of course there are lots of proteins that are used in medicine as well. So I mentioned that antibodies are a type of protein, and lots of medicines are types of antibodies. There's also insulin, which people use in diabetes; it's a protein that is also a therapeutic drug.
Jacob Trefethen:
What actually are proteins? What do they look like and how do they form?
Saloni Dattani:
Proteins are long chains of amino acids. You can sort of think of that as like beads on a string. And then that string, or that chain, is folded into some kind of 3D shape. The string is the protein's backbone, and each bead is an amino acid. Each amino acid has unique features. So as this string folds into a structure, you can kind of imagine that maybe happening at a small scale — maybe there's like a little helix of the string in some place, or maybe there are two parallel strings next to each other. But imagine that... we have to kind of zoom out and this whole 3D shape of the protein could also be connected to another protein; it could be two proteins together, making a protein complex.
Jacob Trefethen:
How is that made? I know I eat some protein, but I think we make some too.
Saloni Dattani:
That's right. So you have lots of DNA in your cells, and the DNA, which is the code of life, is the instructions for which proteins to make and how they should look. The DNA is transcribed into RNA, which is typically this temporary molecule, and then the RNA is then translated into protein by ribosomes. They sort of form one-by-one into this chain, and then rapidly fold into a much bigger structure.
This was kind of interesting to me because when I was reading this, I was thinking, okay, how did the first protein that was ever discovered look? What did people think when they first saw it? And that was fascinating because the first protein whose structure was determined was in 1958, and that was myoglobin. This was determined by John Kendrew, a British scientist. When he discovered this, it was only four years after the discovery of DNA's structure — DNA is of course very beautiful; it has this symmetrical structure, of this helix. And he was really disappointed when he figured out what myoglobin looked like. He wrote in his paper: “Perhaps the most remarkable features of the molecule are its complexity and its lack of symmetry.”
Jacob Trefethen:
Oh no, it's ugly.
Saloni Dattani:
But in hindsight, the irregularity is exactly what makes proteins so powerful. It's not really like DNA, which has this kind of linear messaging — it has the code, and then the code just linearly turns into RNA. But a protein is actually doing multiple things. It's in the cell being bombarded sometimes with lots of different molecules, and it needs to be able to recognise these different shapes and structures, and sometimes, it has multiple functions — and this function of every protein depends on that 3D structure.
The folded shape means that there are like little pockets, grooves and surfaces that the protein uses to bind to other molecules, or carry out specific chemical reactions, or even receive signals and then change shape in response. That means the same protein molecule might be doing multiple things at once. It could be doing a chemical reaction, but also binding to something else, and then when it gets some regulatory signal, it could be changing shape and stopping that chemical reaction from happening.
Jacob Trefethen:
So there's benefits to being a weird blob. There's nothing wrong with being a weird blob.
Saloni Dattani:
I thought it would be fun if we both share some fun facts about proteins. I found these from the book Biology by the Numbers, which is a great textbook, and it's also free online. The authors create these rough estimates and pull together key numbers on lots of different things related to cell biology. Some of them are rough estimates, but they're kind of our best guess right now.
Jacob Trefethen:
Hit me.
Saloni Dattani:
Alright, first one, how many proteins are in a human cell?
Jacob Trefethen:
They're busy, so I'm going to guess a lot. And I'm going to guess it depends on the cell, but I will go with a hundred million.
Saloni Dattani:
That is a lot, and it does depend on the cell. But the estimate for the average number is ten billion proteins per cell.
Jacob Trefethen:
Oh no. Two orders of magnitude wrong, not a good start. Okay, well, I've got one. Which is bigger: the protein or the mRNA that codes for the protein?
Saloni Dattani:
Um... surely the protein is bigger, no? Why would the instructions be bigger than the protein?
Jacob Trefethen:
That's what I always think, and it's the other way around. So the mRNA is bigger — you look at them side by side - well, images of 'em - and the mRNA is like 10 times bigger. Because each amino acid is coded for by three nucleotides, and the nucleotides themselves are bigger and heavier. So it's counterintuitive to me, but you know, it makes sense, I guess, when you think about it physically.
Saloni Dattani:
That does make sense... well, I don't know if that makes sense. I feel like I need to think about this more.
Jacob Trefethen:
Yeah, it doesn't make sense from a computer science point of view, but from a physical point of view it feels like, yeah.
Saloni Dattani:
Right.
I have one. So, you know, as a small person, I wanted to find out which protein was the smallest. Do you have any guesses?
Jacob Trefethen:
The protein that's the smallest? Well, the definition of a protein... I wonder if I'm allowed to have- it's got to have at least two amino acids, so I know it's not going to be less than two, but that probably wouldn't count as a protein because it wouldn't fold into anything, wouldn't have much function. So I'm going to guess philosophically, two, and then, literally, more than two.
Saloni Dattani:
Well, you're right. I think the typical definition of a protein is something that floats on its own in water and can fold into a stable shape. If you use that definition, then the smallest ones are some 20 to 30 amino acids long. There are actually lots of really tiny proteins, and these tiny proteins are called "micro proteins", and they're less than a hundred amino acids or so. One example that's actually even smaller than 20 or 30 is somatostatin, which is a hormone that controls other hormones — so it controls growth hormone and insulin — and that's only 14 amino acids long.
Jacob Trefethen:
Oh wow, it's that small. Oh okay.
Saloni Dattani:
Right. It still has a stable shape, because parts of the chain are connected to each other. So it's not considered a typical protein, but it's a peptide and it's very small.
Jacob Trefethen:
Got it, okay. What's the biggest? I think you know the answer to this one.
Saloni Dattani:
I think I do. Is it titin?
Jacob Trefethen:
It's titin. That's the biggest human protein at least, I don't know outside of humans. But that one is 33,000 amino acids long.
Saloni Dattani:
I got one. What's the most abundant protein on earth?
Jacob Trefethen:
I am going to guess it has something to do with photosynthesis, because that seems like one of the biggest functions on earth.
Saloni Dattani:
Very good guess. So it's kind of a tie, and we're not really sure which one is more abundant, so that was a bit of a trick question.
Jacob Trefethen:
Oh wow.
Saloni Dattani:
But one of them is RuBisCO, and that is used in photosynthesis; it's used to grab carbon from the air and turn it into useful organic material. And that's used by all photosynthetic organisms. And scientists estimate that there are about five kilograms of RuBisCO per person on earth.
Jacob Trefethen:
Oh my god. What?! Wow.
Saloni Dattani:
I guess there are a lot of plants.
Jacob Trefethen:
Yeah, fair enough. They're winning. They're winning... for now...
Saloni Dattani:
There's actually the second, which might be ahead. We're not sure-
Jacob Trefethen:
Oh right.
Saloni Dattani:
-and that is collagen. That is used as a kind of structural protein, and it makes up about 30% of the protein mass in your body — so about three kilograms of collagen per person. But it's not just humans that have collagen, it's also the livestock and all animals. That means there's- well, the total number- the total mass of livestock is also enormous, right? And so this means there's roughly four to six kilograms of collagen per person on earth.
Jacob Trefethen:
Ready for another fun fact?
Saloni Dattani:
Yes.
Jacob Trefethen:
Well, enzymes are a type of protein that speed up reactions... so how much do you think enzymes speed up reactions?
Saloni Dattani:
Mmm... a thousand times, maybe? Two thousand? I feel like... a lot. But I don't know.
Jacob Trefethen:
A lot. A lot. And I bet some do a thousand, but if you're really looking at the best of the best, we're talking billions of times, and possibly trillions of times, so we're talking millions of reactions per second per enzyme in some cases, and just totally changing what is happening at the molecular level.
Saloni Dattani:
That's crazy. That means, I guess, some reactions just wouldn't happen if the enzymes weren't there.
Jacob Trefethen:
Oh, absolutely. Yeah. I mean, statistically speaking, yeah.
Saloni Dattani:
So we were talking about protein folding the other day, and I was thinking: well, how fast do proteins fold into shape? Do you have any guesses?
Jacob Trefethen:
Oh... that is a tough one. The folding has to happen quickly, otherwise they'll get distracted by other forces. So I will go with tenths of seconds, no, hundredths of seconds.
Saloni Dattani:
Pretty close. So, on average, proteins fold in milliseconds, but some proteins fold really quickly, in micro seconds, which are a millionth of a second. And I guess you're right that it really does have to happen fast, because there's so much other stuff going on in the cell. It could just be bombarded with something else before it folds.
Jacob Trefethen:
Yeah, well, no fun.
Saloni Dattani:
How fast are enzymes colliding with other molecules in the cell? Or how many collisions are there per second?
Jacob Trefethen:
Okay. I have the sense that things are just crazy up in there and everyone's sort of bumping around. So I'm going to say a thousand collisions a second.
Saloni Dattani:
Well, you were right with the idea.
Jacob Trefethen:
Oh no, I should have just said "A lot."
Saloni Dattani:
But I think the estimate is 500,000 molecules are colliding with an enzyme per second.
Jacob Trefethen:
Wow.
Saloni Dattani:
And that's a lot! And that makes me think that proteins have to be really specific in how they bind to their targets. It's like, you know, if you're at a really crowded party and you're trying to find a friend, you would just bump into so many people before you actually find your friend. So you have to actually be able to recognise them among the 500,000 random strangers around you.
Jacob Trefethen:
Yep. That's tricky. Okay, Saloni, what's your favourite protein?
Saloni Dattani:
My favourite protein is tubulin. It's part of microtubules. The microtubules are kinda the skeletons of your cells... That sounds a bit grim, actually. But they are basically formed of these hollow tubes that are made of this protein, and each of the little structures is kind of like a tiny corn kernel. That tube can sort of assemble and disassemble in response to signals, and that means that the entire skeleton can kind of assemble and disassemble... which means the whole cell can change its shape or its size and move around, because of these microtubules. The microtubules also act as tracks to move things around, so they're a bit like a cellular railway or something, which I think is just super cool. And I remember learning about this in my undergrad and just seeing some diagrams and thinking, wow, that's amazing.
Jacob Trefethen:
That's a good one. I have an even better one though, which is… gluten in bread! Woo! I'm a bread guy.
Saloni Dattani:
That's a good one.
Jacob Trefethen:
We each have our favourites.
Saloni Dattani:
This was the first of a series of mini episodes we're doing on proteins. Stay tuned for our next episode on the history of Insulin. And if you like this, share it with your friends and subscribe.