AlphaFold 2: Revolutionizing Protein Folding Solutions in Biology

AlphaFold 2 revolutionized protein folding by predicting 3D structures from amino acid sequences in seconds, transforming structural biology.

### Breakthrough in Protein Folding: The AlphaFold Revolution
* 🧬 AlphaFold 2 has achieved what was once deemed **impossible**: accurately predicting protein folding, marking a **monumental breakthrough** in structural biology and science at large.
* 🔬 Proteins, the **essential workhorses of biology**, are specified by their amino acid sequences, and their **3D structure directly determines their function** in biological processes and drug interactions.
* 📊 For over 50 years, the protein folding problem has challenged scientists, with the first articulation of its complexity made by Nobel Prize winner **Christian Anfinsen** in 1972, likening it to **Fermat's Last Theorem for biology**.
* ⏳ Traditionally, determining a protein's structure required painstaking experimental methods, taking an entire PhD student **years to crystallize and visualize just one protein**, while AlphaFold 2 can predict the 3D structure in **mere seconds**.
* 🌍 Over the Christmas period, AlphaFold 2 successfully predicted the structures of all **20,000 proteins in the human proteome**, revolutionizing how structural biologists approach their work by allowing them to "**look up**" protein structures like a **Google search**.
* ⚙ The development of AlphaFold involved integrating **over 30 algorithms**, leveraging constraints from **physics and evolutionary biology**, and innovatively expanding its training set through **self-distillation**, which enhanced its **predictive capabilities**.
* 🔄 Unlike its predecessor, AlphaFold 1, which produced a matrix of distances, AlphaFold 2 operates end-to-end, directly converting amino acid sequences into 3D structures, showcasing the system's ability to **learn constraints more effectively than human designers**.
* 🌌 This journey from AlphaGo to AlphaFold illustrates the evolution of AI from **imitation learning to self-supervised learning**, emphasizing the importance of **building and understanding complex systems** in the pursuit of **scientific advancement**.

So, here's another problem that was thought to be impossible to solve, which is protein folding, and AlphaFold, or specifically AlphaFold 2, did just that. It solved protein folding. I think it's one of the biggest breakthroughs, certainly in the history of structural biology, but in general in science. Maybe from a high level, what is it and how does it work? And then we can ask some fascinating questions after. Sure. So, maybe to explain it to people not familiar with protein folding is, you know, I first of all explain proteins, which is, you know, proteins are essential to all life. Every function in your body depends on proteins. Sometimes they're called the workhorses of biology. And if you look into them, and I've, you know, obviously as part of AlphaFold, I've been researching proteins and structural biology for the last few years, you know, they're amazing little bio-nano machines, proteins. They're incredible. If you actually look at little videos of how they work, animations of how they work, and proteins are specified by

their genetic sequence called their amino acid sequence. So, you can think of it with their genetic makeup, and then in the body, in nature, they, when they fold up into a 3D structure. So, you can think of it as a string of beads, and then they fold up into a ball. Now, the key thing is you want to know what that 3D structure is, um, because the structure, the 3D structure of a protein, uh, is what helps to determine what does it do, the function it does in your body, uh, and also if you're interested in drug drugs or disease. You need to understand that 3D structure because if you want to target something with a drug compound about to block something the protein's doing, uh, you need to understand where it's going to bind on the surface of the protein. So, obviously, in order to do that, you need to understand the 3D structure. So, the structure is mapped to the function. The structure is mapped to the function, and the structure is obviously somehow

specified by the amino acid sequence, and that's the protein folding problem. Can you just, from the amino acid sequence, the one-dimensional string of letters, can you immediately computationally predict the 3D structure, right? And this has been a Grand Challenge in biology for over 50 years. So, I think it was first articulated by Christian Anfinsen, a Nobel Prize winner in 1972, as part of his Nobel Prize-winning lecture. And he just speculated this should be possible to go from the amino acid sequence to the 3D structure, but he didn't say how. So, I, you know, it's being described to me as equivalent to Fermat's Last Theorem but for biology, right? You should, as somebody that very well might win the Nobel Prize in the future, but outside of that, you should do more of that kind of thing in the margin, just put random things that will take like 200 years to solve, set people off for 200 years. It should be

possible and just don't give any DET exactly. I think everyone exactly should be. I'll have to remember that for future. So yeah, so he said off, you know, with this one throwaway remark just like Fermat, you know, he set off this whole 50e field really of computational biology. And they had, you know, they got stuck, they hadn't really got very far with doing this and um until now, until Alpha came along. This is done experimentally, right, very painstakingly. So the rule of thumb is, and you have to like crystallize the protein, which is really difficult. Some proteins can't be crystallized like membrane proteins. And then you have to use very expensive electrom microscopes or x-ray crystallography machines, really painstaking work to get the 3D structure and visualize the 3D structure. So the rule of thumb in experimental biology is that it takes one PhD student their entire PhD to do one protein. And with Alpha 2, we were able to predict

the 3D structure in a matter of seconds. Um, and so we were, you know, over Christmas, we did the whole human proteome or every protein in the human body or 20,000 proteins. So the human proteome is like the equivalent of the human genome but on protein space and, uh, and sort of revolutionize really what a structural biologist can do because now, um, they don't have to worry about these painstaking experimentals, you know, should they put all of that effort in or not. They can almost just look up the structure of their proteins like a Google Search. And so there's a data set on which it's trained and how to map this amino acid. First of all, it's incredible that a protein, this little chemical computer, is able to do that computation itself in some kind of distributed way and do it very quickly. That's a weird thing. And they evolve that way because, you know, in the beginning, I mean, that's a great invention, just the protein itself of Earth, and then they, there's, I think

probably a history of like, uh, they evolved, uh, to have many of these proteins, and those proteins figure out how to be computers themselves in such a way that you can create structures that can interact in complex with each other in order to form high-level functions. I mean, it's a weird system that they figured it out well for sure. I mean, we, you know, maybe we should talk about the origins of life too, but proteins themselves, I think, are magical and incredible, uh, uh, uh, as I said, little bionano machines, and um, and, and actually Leventhal, who was another scientist, uh, contemporary of Anenson, uh, he, he, he coined this Leventhal, what became known as Lal's Paradox, which is exactly what you're saying. He calculated roughly a pro, an average protein, which is maybe 2,000 amino acids bases long, is um, is, is can fold in maybe 10 to the power 300 different confirmations. So, there's 10 the^ 300 different ways that

protein could fold up, and yet somehow in nature, physics solves this in a matter of milliseconds. So, proteins fold up in your body in, you know, sometimes in fractions of a second. So, physics is somehow solving that search problem. Maybe you can give some interesting sort of beautiful things to you about these early days of AlphaFold, of solving this problem, because unlike games, this is real physical systems that are less amenable to self-play type of mechanisms. Sure, the size of the dataset is smaller than you might otherwise like, so you have to be very clever about certain things. Is there something you could speak to, um, what was very hard to solve and what are some beautiful aspects about the solution? Yeah, I would say AlphaFold is the most complex and also probably most meaningful system we've built so far. So, it's been an amazing time, actually, in the last, you know, two, three years to see that come through because, um, as we talked about earlier, you know, games is what we started on, uh, at building things.

like AlphaGo and AlphaZero, but really the ultimate goal was to, um, not just to crack games. It was just to build, use them to bootstrap General Learning Systems we could then apply to real-world challenges. Specifically, my passion is scientific challenges like protein folding, and then AlphaFold, of course, is our first big proof point of that. And so, um, you know, in terms of the data, uh, and the amount of innovations that had to go into it, we, you know, it was like more than 30 different component algorithms needed to be put together to crack the protein folding. Um, I think some of the big innovations were that, um, kind of building in some hardcoded constraints around physics and evolutionary biology, um, to constrain sort of things like the bond angles, uh, uh, uh, in the protein and things like that. Um, a lot, but not to impact the learning system, so still allowing, uh, the system to be able to learn the physics, uh, itself, um, from the examples that we had. And the examples, as you say, there are

only about 150,000 proteins. Even after 40 years of experimental biology, only around 150,000 proteins have been. The structures have been found out about, so that was our training set, which is much less than normally we would like to use, but using various tricks, things like self-distillation, so actually using AlphaFold predictions, some of the best predictions that it thought was highly confident in, we put them back into the training set right to make the training set bigger. That was critical to AlphaFold working, so there was actually a huge number of different innovations like that that were required to ultimately crack the problem. AlphaFold 1, what it produced was a disr, so a kind of a matrix of the pairwise distances between all of the molecules in the protein, and then there had to be a separate optimization process to create the 3D structure. What we did for AlphaFold 2 is make it truly end-to-end, so we went straight from the amino

acid sequence of uh bases to uh the 3D structure directly without going through this intermediate step. And in machine learning, what we've always found is that the more end-to-end you can make it, the better the system. And it's probably because, um, we, you know, in the end, the system is better at learning what the constraints are than we are as the human designers of specifying it. So anytime you can let it flow end-to-end and actually just generate what it is you're really looking for, in this case, the 3D structure, uh, you're better off than having this intermediate step, which you then have to handcraft the next step for. So, um, so it's better to let the gradients and the learning flow all the way through the system, um, from the endpoint, the end output you want, to the inputs. So that's a good way to start on a new problem, handcraft a bunch of stuff, add a bunch of manual constraints with a small intent learning piece or a small learning piece, and grow that learning.

piece until it consumes the whole thing. That's right. And so you can also see, you know, this is a bit of a method we've developed over doing many sort of successful Alpha. We call them alpha x projects, right? Is, and the easiest way to see that is the evolution of alpha go to Alpha zero. So Alpha go was a learning system, but it was specifically trained to only play go, right? So, uh, and what we want to do in with the first version of alpha go is just get to world champion performance, no matter how we did it, right? And then, and then of course Alpha go zero, we, we, we remove the need to use human games as a starting point, right? So it, it could just play against itself from random starting point from the beginning. So that removed the, the need for human knowledge, uh, about go. And then finally Alpha zero then generalized it so that any things we had in there, the system, including things like symmetry of the go board, uh, were removed so the alpha zero could play from scratch any two-player game. And then muzero, which is

the final, our latest version of that set of things was then extending it so that you didn't even have to give it the rules of the game. It would learn that for itself, so it could also deal with computer games as well as board games. So, that line of Alpha Go, Alpha Go Zero, Alpha Zero, Mu Zero, that's the full trajectory of what you can take from imitation learning to full self-supervised learning. Yeah, exactly, and learning the high structure of the environment you're put in from scratch, right? And bootstrapping it through self-play, yourself. But the thing is, it would have been impossible, I think, or very hard for us to build Alpha Zero or Mu Zero first out of the box, even psychologically, because you have to believe in yourself for a very long time. You're constantly dealing with doubt because a lot of people say that it's impossible to exact. So, it's hard enough just to do Go, as you were saying. Everyone thought that was impossible or at least a decade away.

from when we did it back in 2015, 204, you know, 2016, and um, and so yes, it would have been psychologically probably very difficult, as well as the fact that, of course, we learn a lot by building alphao first, right? So it's, I think this is why I call AI an engineering science. It's one of the most fascinating science disciplines, but it's also an engineering science in the sense that, unlike Natural Sciences, um, the phenomenon you're studying doesn't exist out in nature. You have to build it first, so you have to build the artifact first, and then you can study how and pull it apart and how it works.

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AlphaFold's Breakthrough in Protein Folding

AlphaFold 2 has successfully solved the long-standing problem of protein folding, a key challenge in biology for over 50 years.

Proteins, essential for all life, are specified by their amino acid sequence and fold into a 3D structure, which determines their function.

Understanding this 3D structure is crucial for drug targeting and disease treatment, making AlphaFold's achievement a significant breakthrough in structural biology and science as a whole.

The Impact of Alpha on Protein Structure Prediction

Alpha's arrival revolutionized the field of computational biology by predicting the 3D structure of proteins in seconds, a task that traditionally took PhD students years.

The human proteome, consisting of 20,000 proteins, was mapped over a short period, changing the approach for structural biologists.

The unique ability of proteins to perform complex computations and interact with each other has been key to their evolutionary success and the development of high-level functions.

AlphaFold has revolutionized protein folding, solving the complex problem in fractions of a second using innovative algorithms and hardcoded constraints.

With only 150,000 proteins in its training set, AlphaFold used self-distillation and other tricks to enhance its learning.

The transition from AlphaFold 1's pairwise distance matrix to an end-to-end approach in AlphaFold 2 marked a significant advancement in predicting 3D protein structures.

End-to-end learning is more effective as it allows the system to directly generate the desired output, such as a 3D structure, without intermediate steps.

This approach helps the system learn constraints better than human designers.

The method has been successfully applied in Alpha projects, evolving from Alpha Go to Alpha Zero, which removed the need for human knowledge and generalized the learning to any two-player game.

The latest AI versions have evolved to learn game rules independently, transitioning from imitation learning to self-supervised learning.

This trajectory includes Alpha Go, Alpha Go Zero, Alpha Zero, and Mu Zero, showcasing the power of self-play and bootstrapping.

The journey to develop these models was psychologically challenging, requiring a strong belief in their potential and learning from the earlier versions.