9 ms·

What's next for AlphaFold and the AI protein-folding revolution

136 points by digital55 5y ago

fabian2k 5y ago
I found it interesting that AlphaFold can't reliably predict the structures for mutations that disrupt structure. The explanation makes a lot of sense though. It is sometimes important to remind oneself that the selection of protein structures that exist in nature and that we determined experimentally is biased. Nature doesn't like proteins that misfold because they can easily cause trouble. And proteins with less defined structures are generally harder to solve with the usual methods like X-ray crystallography. The list of protein structures we know isn't a representative sample of all possible protein structures, it's mostly structures that are useful in nature and that we can determine with the methods we have available.
- alan-hn 5y ago
  >proteins with less defined structures are generally harder to solve with the usual methods like X-ray crystallography What do you mean by 'proteins with less defined structures'? I'm not familiar with what this phrase could mean, could you please expand on this concept?
  - fabian2k 5y ago
    Less defined means flexible in this case. So either parts that are completely random on their own, or parts that can adopt multiple different structures. There are also intrinsically disordered proteins that have no defined structure when they are on their own, that's essentially like a piece of string that is almost completely flexible. Those proteins can still adopt a specific well-defined structure if they bind to something else.
    - alan-hn 5y ago
      So does flexible mean that there may be different amino acids in a portion of the peptide? From my understanding, when flexibility is discussed in terms of proteins we're talking about rigid vs flexible side chains which can move or rotate along specific bonds So for the intrinsically disordered ones, are you mainly talking about the secondary or tertiary structures? My assumption based on your statement is that we're keeping the same primary structure (order of amino acids) but they don't have many (if any at all) intermolecular interactions? Would it be safe to assume that you're referring to shorter polypeptide rather than large proteins?
      - dekhn 5y ago
        in disordered proteins, there is no permanent tertiary structure. they may have some secondary structure, but the relations of those structural elements can change in time. It does not mean the seuqence has variation in it.
        alan-hn 5y ago
        Does this mean that they have multiple conformational states with similar energies that are easy for it to transition between? How different are the states and is this how the protein normally does its proteiny stuff?
        dekhn 5y ago
        yes, I would say that intrisnically disordered proteins adopt something like an unfolded state, which is to say that they can visit a wide range of structures that are at similar energy levels, all of which are accessible at ~room temp. I can't really answer in more detail because all the ID proteins are fairly different an dhow they do their job is hard to understand compared to stable static "rocks" like enzyymes.
        throwawaybio3 5y ago
        Enzymes aren't stable and static -- usually in their active site they have significant conformational changes that enable catalysis of the relevant chemical reaction. It's quite a problem that we don't have general robust ways of directly elucidating those transient structures, a lot of our understanding of catalysis is still held back or slow-evolving because we can only use indirect and cumbersome methods (like isotopic mutation + laser IR) I would consider most enzymes to be intrinsically disordered at their active sites.
        dekhn 5y ago
        No enzymes are not intrinsically disordered at their active sites. They are highly ordered. Most enzymes don't undergo large changes- they accept a molecule, do their business, and release it. You're thinking of other proteins like motor proteins which under go large, controlled conformational changes. The active site is structured to stabilize the transition state of the affected molecule and move it from one state to the next in the chemical reaction. That requires very specific shapes and correlated changes. But of course, this being biology, you can remove all 3 active site residues in a serine protease catalytic triad, and still see proteolysis because the protein, when it binds the substrate, forces the subtrate into its transition pathway. People have been working on these things for quite some time- I saw talks about time-resolved crystallography of active sites, and while they say "significant structure changes", they really only mean localized breathing-like motions, not massive rotations of entire domains.
  - dekhn 5y ago
    think loose floppy piles of spaghetti instead of well-defined rocks.
  - tintor 5y ago
    Example by analogy: Flat tire has less defined structure, and can take many shapes. Inflated tire has more defined structure, and behaves more predictably.
  - jostmey 5y ago
    The same protein can deform into multiple different 3D shapes, called conformations. Some proteins are rigid and exist almost exclusively in a single conformation. It is probably easier to determine the 3D structure of proteins with a single, dominant conformation. Other proteins don't have well defined conformations, and are more like a tangle of rope that can bend in many different ways
    - panabee 5y ago
      thanks for the explanation. what are the biggest factors influencing conformation? what are the best ways today for imaging proteins with different conformations, and what are the limitations of these methods?
  - abcc8 5y ago
    Many proteins have intrinsically disordered regions that are hypothesized to be directly related to the protein's role in the cell. These regions are termed disordered because current methods used to determine the structure of proteins are unable to resolve a regular structure for these regions in the context of a protein crystal or protein in solution. This publication is an informative review on the topic: https://pubs.acs.org/doi/10.1021/cr400525m https://pubs.acs.org/doi/10.1021/cr400525m
- axg11 5y ago
  Very nicely explained. Also hints at the next big frontier for protein folding: improving the prediction of those disruptive effects.
- flobosg 5y ago
  > I found it interesting that AlphaFold can't reliably predict the structures for mutations that disrupt structure It’s not that surprising given the conceptual background of the method. Since it’s relying on evolutionarily coupled residues, AlphaFold is looking at sets of complementary mutations that keep or rescue a determined structure, i.e. the complete opposite of structural disruption. > The list of protein structures we know isn't a representative sample of all possible protein structures And the same goes for protein sequences.
photochemsyn 5y ago
It's kind of surprising that AlphaFold has some success with random sequences of amino acids: > "Baker’s team gets AlphaFold and RoseTTAFold to “hallucinate” new proteins. The researchers have altered the AI code so that, given random sequences of amino acids, the software will optimize them until they resemble something that the neural networks recognize as a protein. In December 2021, Baker and his colleagues reported expressing 129 of these hallucinated proteins in bacteria, and found that about one-fifth of them folded into something resembling their predicted shape." 20% is not that great but it has potential. One long-standing goal is the de novo design of protein-based industrial catalysts for specific chemical transformations. Proteins from bacteria that live in boiling sulfur vents etc. have been used to some extent, but the idea is that similar proteins could be designed for a much wider variety of industrial processes. As the article notes, specificity remains a challenge (and designed proteins don't approach the efficiency of the evolutionary selected proteins), but it still seems promising. P.S. I'm a bit more skeptical about the drug-design programs. It's not so much that novel drugs can't be designed that bind to the desired targets, it's that they might bind to a whole lot of undesired targets as well, leading to nasty side effects. Now if you could screen against the whole proteome, perhaps.
- flobosg 5y ago
  > 20% is not that great but it has potential. 20% success rate is in line with other protein design methods, though.
  - gfodor 5y ago
    I'd imagine the success rate isn't apples to apples - the real measure is "time, energy, and manpower expenditure needed per generated protein"
    - flobosg 5y ago
      Both measures can be quite similar. Most protein designs can be screened in parallel for solubility and successful designs can be further engineered and tested in a high-throughput manner.
dekhn 5y ago
I just wish people would stop using the word "fold" for this. It's not folding. It's just structure prediction. It's great at structure prediction (static prediction of a single structure) and not at all at the folding process (which is dynamic and rapidly changing).
- flobosg 5y ago
  “Protein fold” and “protein folding” are two different concepts. Folds are structural categories, folding is the biophysical process. But I agree that there are better words out there to name such a tool.
  - dekhn 5y ago
    That's very misleading, as you can see. I believe we should not use the term fold for structural categories as it's a misnaming. It's a historical accident that came about before people began to understand that folding is a process, not an on/off switch. See my work in this area: https://pubmed.ncbi.nlm.nih.gov/24345941/ https://pubmed.ncbi.nlm.nih.gov/24345941/ which is explicitly attempting to simulate an approximate folding pathway(s).
    - flobosg 5y ago
      There are other terms analogous to “fold”, like “topology” (as used in CATH), but they will probably never see widespread use.
      - dekhn 5y ago
        Yup. I've had this discussion repeatedly with the developers of SCOP and the folks who run CASP and they simply will not budge.
      - gilleain 5y ago
        Even 'topology' is a little confusing to those more familiar with the term from maths. For the 'CATH' hierarchical classification, the 'Topology' level is something like the organization of secondary structure in an 'Architecture'. This has some relationship to topology in the general sense, but is a narrower definition. For me, the 'fold' is what happens after 'folding' occurs, but I take the point that it is confusing.
codeflo 5y ago
I think this article does a good job of highlighting the difference between simulations and ML-based approaches. The latter are faster, but have limitations outside of their training parameters. As with everything in ML, broader training data to cover those cases probably helps. Though I would guess some of the problems could be inherent, that there fundamentally is no computational shortcut to this problem, whether you use a neural network or not.
mupuff1234 5y ago
Does Deepmind sell anything? Their site has no mention of any type of offering.
- benrapscallion 5y ago
  They have spun out a drug design company named Isomorphic Labs. [1] [1] https://www.isomorphiclabs.com/ https://www.isomorphiclabs.com/
  - dekhn 5y ago
    amusingly, I work for a pharma and they don't even return our calls. I wonder how seriously they take this business, because if I was selling a product based on this, pharma would be my first customer.
    - pkaye 5y ago
      Must have taken the Google approach and already terminated the product. /s
    - alphabetting 5y ago
      Could be wrong but I think Deepmind sees more value in elite AI/ML talent that Alphafold will draw and help retain than future potential profits on drug discovery. Open sourcing Alphafold and removing commercial restrictions wouldn't make much sense if drug profits were their goal.
      - dekhn 5y ago
        No, isomorphic labs was set up to specifically commercialize this. If their goal is to be a discovery company, they are fairly naive.
        alphabetting 5y ago
        Yeah I know about Isomorphic labs. My point is that talent Alphafold will draw is more valuable than potential drug discovery profits.
xnx 5y ago
Facebook: Releases a tool that makes amusing image mashups Google: Makes revolutionary progress in one of the hardest problems in chemistry
- dekhn 5y ago
  This wasn't Google, it was DeepMind. Google doesn't get any credit for this. I tried to start this project at Google but it conflicted with the Google Health team's goals.
  - bawolff 5y ago
    Its owned by google (alphabet) i think they deserve some props for it.
    - dekhn 5y ago
      google is owned by alphabet. DM and Google are siblings.
      - bawolff 5y ago
        Most people say "google" to mean alphabet.
        algoatecorn 5y ago
        True, but applying that logic in order to give credit to Google is wrong, which is the point of the comment above.
        smueller1234 5y ago
        If one wanted to make a case for that, arguably it's DrepMind's major infrastructure resource consumption that would give Google some credit. I can certainly point to some colleagues in infrastructure engineering who've helped DeepMind folks deal with infrastructure problems. That being said, I'm perfectly happy to just be proud of what DeepMind has achieved. They've been great to interact with when there were shared challenges, and I - and to my knowledge all colleagues around me - aren't very interested in a question of credit assignment.
peter303 5y ago
I see a Nobel Prize around the corner. They arent often given for techniques or computation. But the results are outstanding.

136 points by digital55 5y ago

I found it interesting that AlphaFold can't reliably predict the structures for mutations that disrupt structure. The explanation makes a lot of sense though. It is sometimes important to remind oneself that the selection of protein structures that exist in nature and that we determined experimentally is biased. Nature doesn't like proteins that misfold because they can easily cause trouble. And proteins with less defined structures are generally harder to solve with the usual methods like X-ray crystallography. The list of protein structures we know isn't a representative sample of all possible protein structures, it's mostly structures that are useful in nature and that we can determine with the methods we have available.

alan-hn 5y ago
>proteins with less defined structures are generally harder to solve with the usual methods like X-ray crystallography What do you mean by 'proteins with less defined structures'? I'm not familiar with what this phrase could mean, could you please expand on this concept?
- fabian2k 5y ago
  Less defined means flexible in this case. So either parts that are completely random on their own, or parts that can adopt multiple different structures. There are also intrinsically disordered proteins that have no defined structure when they are on their own, that's essentially like a piece of string that is almost completely flexible. Those proteins can still adopt a specific well-defined structure if they bind to something else.
  - alan-hn 5y ago
    So does flexible mean that there may be different amino acids in a portion of the peptide? From my understanding, when flexibility is discussed in terms of proteins we're talking about rigid vs flexible side chains which can move or rotate along specific bonds So for the intrinsically disordered ones, are you mainly talking about the secondary or tertiary structures? My assumption based on your statement is that we're keeping the same primary structure (order of amino acids) but they don't have many (if any at all) intermolecular interactions? Would it be safe to assume that you're referring to shorter polypeptide rather than large proteins?
    - dekhn 5y ago
      in disordered proteins, there is no permanent tertiary structure. they may have some secondary structure, but the relations of those structural elements can change in time. It does not mean the seuqence has variation in it.
      - alan-hn 5y ago
        Does this mean that they have multiple conformational states with similar energies that are easy for it to transition between? How different are the states and is this how the protein normally does its proteiny stuff?
        dekhn 5y ago
        yes, I would say that intrisnically disordered proteins adopt something like an unfolded state, which is to say that they can visit a wide range of structures that are at similar energy levels, all of which are accessible at ~room temp. I can't really answer in more detail because all the ID proteins are fairly different an dhow they do their job is hard to understand compared to stable static "rocks" like enzyymes.
        throwawaybio3 5y ago
        Enzymes aren't stable and static -- usually in their active site they have significant conformational changes that enable catalysis of the relevant chemical reaction. It's quite a problem that we don't have general robust ways of directly elucidating those transient structures, a lot of our understanding of catalysis is still held back or slow-evolving because we can only use indirect and cumbersome methods (like isotopic mutation + laser IR) I would consider most enzymes to be intrinsically disordered at their active sites.
        dekhn 5y ago
        No enzymes are not intrinsically disordered at their active sites. They are highly ordered. Most enzymes don't undergo large changes- they accept a molecule, do their business, and release it. You're thinking of other proteins like motor proteins which under go large, controlled conformational changes. The active site is structured to stabilize the transition state of the affected molecule and move it from one state to the next in the chemical reaction. That requires very specific shapes and correlated changes. But of course, this being biology, you can remove all 3 active site residues in a serine protease catalytic triad, and still see proteolysis because the protein, when it binds the substrate, forces the subtrate into its transition pathway. People have been working on these things for quite some time- I saw talks about time-resolved crystallography of active sites, and while they say "significant structure changes", they really only mean localized breathing-like motions, not massive rotations of entire domains.
- dekhn 5y ago
  think loose floppy piles of spaghetti instead of well-defined rocks.
- tintor 5y ago
  Example by analogy: Flat tire has less defined structure, and can take many shapes. Inflated tire has more defined structure, and behaves more predictably.
- jostmey 5y ago
  The same protein can deform into multiple different 3D shapes, called conformations. Some proteins are rigid and exist almost exclusively in a single conformation. It is probably easier to determine the 3D structure of proteins with a single, dominant conformation. Other proteins don't have well defined conformations, and are more like a tangle of rope that can bend in many different ways
  - panabee 5y ago
    thanks for the explanation. what are the biggest factors influencing conformation? what are the best ways today for imaging proteins with different conformations, and what are the limitations of these methods?
- abcc8 5y ago
  Many proteins have intrinsically disordered regions that are hypothesized to be directly related to the protein's role in the cell. These regions are termed disordered because current methods used to determine the structure of proteins are unable to resolve a regular structure for these regions in the context of a protein crystal or protein in solution. This publication is an informative review on the topic: https://pubs.acs.org/doi/10.1021/cr400525m https://pubs.acs.org/doi/10.1021/cr400525m
axg11 5y ago
Very nicely explained. Also hints at the next big frontier for protein folding: improving the prediction of those disruptive effects.
flobosg 5y ago
> I found it interesting that AlphaFold can't reliably predict the structures for mutations that disrupt structure It’s not that surprising given the conceptual background of the method. Since it’s relying on evolutionarily coupled residues, AlphaFold is looking at sets of complementary mutations that keep or rescue a determined structure, i.e. the complete opposite of structural disruption. > The list of protein structures we know isn't a representative sample of all possible protein structures And the same goes for protein sequences.

photochemsyn 5y ago

It's kind of surprising that AlphaFold has some success with random sequences of amino acids: > "Baker’s team gets AlphaFold and RoseTTAFold to “hallucinate” new proteins. The researchers have altered the AI code so that, given random sequences of amino acids, the software will optimize them until they resemble something that the neural networks recognize as a protein. In December 2021, Baker and his colleagues reported expressing 129 of these hallucinated proteins in bacteria, and found that about one-fifth of them folded into something resembling their predicted shape." 20% is not that great but it has potential. One long-standing goal is the de novo design of protein-based industrial catalysts for specific chemical transformations. Proteins from bacteria that live in boiling sulfur vents etc. have been used to some extent, but the idea is that similar proteins could be designed for a much wider variety of industrial processes. As the article notes, specificity remains a challenge (and designed proteins don't approach the efficiency of the evolutionary selected proteins), but it still seems promising. P.S. I'm a bit more skeptical about the drug-design programs. It's not so much that novel drugs can't be designed that bind to the desired targets, it's that they might bind to a whole lot of undesired targets as well, leading to nasty side effects. Now if you could screen against the whole proteome, perhaps.

flobosg 5y ago
> 20% is not that great but it has potential. 20% success rate is in line with other protein design methods, though.
- gfodor 5y ago
  I'd imagine the success rate isn't apples to apples - the real measure is "time, energy, and manpower expenditure needed per generated protein"
  - flobosg 5y ago
    Both measures can be quite similar. Most protein designs can be screened in parallel for solubility and successful designs can be further engineered and tested in a high-throughput manner.

dekhn 5y ago

I just wish people would stop using the word "fold" for this. It's not folding. It's just structure prediction. It's great at structure prediction (static prediction of a single structure) and not at all at the folding process (which is dynamic and rapidly changing).

flobosg 5y ago
“Protein fold” and “protein folding” are two different concepts. Folds are structural categories, folding is the biophysical process. But I agree that there are better words out there to name such a tool.
- dekhn 5y ago
  That's very misleading, as you can see. I believe we should not use the term fold for structural categories as it's a misnaming. It's a historical accident that came about before people began to understand that folding is a process, not an on/off switch. See my work in this area: https://pubmed.ncbi.nlm.nih.gov/24345941/ https://pubmed.ncbi.nlm.nih.gov/24345941/ which is explicitly attempting to simulate an approximate folding pathway(s).
  - flobosg 5y ago
    There are other terms analogous to “fold”, like “topology” (as used in CATH), but they will probably never see widespread use.
    - dekhn 5y ago
      Yup. I've had this discussion repeatedly with the developers of SCOP and the folks who run CASP and they simply will not budge.
    - gilleain 5y ago
      Even 'topology' is a little confusing to those more familiar with the term from maths. For the 'CATH' hierarchical classification, the 'Topology' level is something like the organization of secondary structure in an 'Architecture'. This has some relationship to topology in the general sense, but is a narrower definition. For me, the 'fold' is what happens after 'folding' occurs, but I take the point that it is confusing.

codeflo 5y ago

I think this article does a good job of highlighting the difference between simulations and ML-based approaches. The latter are faster, but have limitations outside of their training parameters. As with everything in ML, broader training data to cover those cases probably helps. Though I would guess some of the problems could be inherent, that there fundamentally is no computational shortcut to this problem, whether you use a neural network or not.

mupuff1234 5y ago

Does Deepmind sell anything? Their site has no mention of any type of offering.

benrapscallion 5y ago
They have spun out a drug design company named Isomorphic Labs. [1] [1] https://www.isomorphiclabs.com/ https://www.isomorphiclabs.com/
- dekhn 5y ago
  amusingly, I work for a pharma and they don't even return our calls. I wonder how seriously they take this business, because if I was selling a product based on this, pharma would be my first customer.
  - pkaye 5y ago
    Must have taken the Google approach and already terminated the product. /s
  - alphabetting 5y ago
    Could be wrong but I think Deepmind sees more value in elite AI/ML talent that Alphafold will draw and help retain than future potential profits on drug discovery. Open sourcing Alphafold and removing commercial restrictions wouldn't make much sense if drug profits were their goal.
    - dekhn 5y ago
      No, isomorphic labs was set up to specifically commercialize this. If their goal is to be a discovery company, they are fairly naive.
      - alphabetting 5y ago
        Yeah I know about Isomorphic labs. My point is that talent Alphafold will draw is more valuable than potential drug discovery profits.

xnx 5y ago

Facebook: Releases a tool that makes amusing image mashups Google: Makes revolutionary progress in one of the hardest problems in chemistry

dekhn 5y ago
This wasn't Google, it was DeepMind. Google doesn't get any credit for this. I tried to start this project at Google but it conflicted with the Google Health team's goals.
- bawolff 5y ago
  Its owned by google (alphabet) i think they deserve some props for it.
  - dekhn 5y ago
    google is owned by alphabet. DM and Google are siblings.
    - bawolff 5y ago
      Most people say "google" to mean alphabet.
      - algoatecorn 5y ago
        True, but applying that logic in order to give credit to Google is wrong, which is the point of the comment above.
        smueller1234 5y ago
        If one wanted to make a case for that, arguably it's DrepMind's major infrastructure resource consumption that would give Google some credit. I can certainly point to some colleagues in infrastructure engineering who've helped DeepMind folks deal with infrastructure problems. That being said, I'm perfectly happy to just be proud of what DeepMind has achieved. They've been great to interact with when there were shared challenges, and I - and to my knowledge all colleagues around me - aren't very interested in a question of credit assignment.

peter303 5y ago

I see a Nobel Prize around the corner. They arent often given for techniques or computation. But the results are outstanding.