17 ms·

What is protein folding? A brief explanation

314 points by jasoncrawford 6y ago

DoreenMichele 6y ago
This is the TLDR from the article of the answer to the question "What is protein folding?": If a protein is essentially a self-assembling nanomachine, then the main purpose of the amino acid sequence is to produce the unique shape, charge distribution, etc. that determines the protein’s function. The article goes on to talk about other things, like "What if, instead of measuring a protein’s structure, we could predict it?" and that's cool, but it's sort of outside of the scope of the question posed in the title. I only kind of skimmed that section because it's about this project that is trying to figure out how to predict what shapes proteins fold into. Nifty tech, but not something I care a whole lot about. (Edit: If that tech interests you, there's also this on HN today: https://news.ycombinator.com/item?id=25253488 https://news.ycombinator.com/item?id=25253488 and I imagine that's why this was even posted -- because some people are probably wondering "What's a 101 explanation of protein folding?") Not covered by the article: Misfolded proteins are the crux of the problem with most genetic disorders. Your body produces this string of protein sequences and it fails to fold up into the unique shape that makes it a useful tool that does a specific job. (I always think of some old cartoon where two kids are playing with "gender neutral spiffy spiffy high minded description" toy from Switzerland -- think LEGOS only blocks you string together and bend as you see fit -- and their two mothers are talking and then one of the kids folds the bendable blocks into the shape of a gun and says "Bang" and one of the moms is all "Never mind.") Chemical derangement of the cell can interfere with protein folding. You have these little factories inside the cell that produce protein strings and as they come out, if the climate is chemically deranged (usually pH balance or salt imbalance are the culprits), then it won't fold. It just lays there, a stringy useless mess of protein. When you cook an egg, the egg white turns white and solidifies due to proteins being denatured. Denatured means they got unfolded. Sometimes when a protein is denatured -- unfolded -- it's reversible. Sometimes -- like with egg whites -- it's not. So in some cases if you could figure out why the protein is failing to fold properly, the body can potentially re-use denatured proteins and turn them back into working nanomachines. And sometimes it can't and then it has to go to some kind of garbage chute in the cell and some serious genetic disorders involve a failed garbage chute, so misfolds can't be effectively removed from the cell, which is a really huge problem. The "garbage chute" is some thing that basically digests the proteins.
- deepfates 6y ago
  thank you
- flobosg 6y ago
  You raise very good points about the role of protein folding and quality control in disease. But folding by itself is essentially a physicochemical process. A protein will fold (or its mutant will misfold) within a cell just like it would do it in a test tube. Don't underestimate the role of structure prediction in human disease. There are proteins known to be involved in disorders where a structure has been impossible to determine by experimental methods (membrane proteins are a known example). And there are still plenty of barely characterized proteins where a structural model might shed light on their function. > Your body produces this string of protein sequences A small nitpick: you meant "string of amino acids". In other words, a protein sequence. > Sometimes -- like with egg whites -- it's not. Under the right conditions even proteins in coagulated egg white can be renatured.
  - DoreenMichele 6y ago
    TIL: Under the right conditions even proteins in coagulated egg white can be renatured. A small nitpick: you meant "string of amino acids". In other words, a protein sequence Thank you. You are correct. Don't underestimate the role of structure prediction in human disease. I'm not. I just don't really find the tech behind it fascinating. When they start coming out with articles saying "This project has successfully predicted X and this is clinically useful in this way," I'm sure I will read it on the edge of my seat like a gripping thriller.
    - COGlory 6y ago
      It's going to take quite some time until this gets accepted at the same level of experimental data, if ever.
      - DoreenMichele 6y ago
        I honestly have no idea what your point is.
whoisjuan 6y ago
That was an awesome explanation of this concept. I wish more complex concepts were explained with so much clarity and concision.
dukeofdoom 6y ago
Is there a simple python example, with protein Data and an Algorithm to fold it.
- DoreenMichele 6y ago
  I don't actually know. I'm just futzing around online while unable to get to sleep. But I googled "python play with protein folding" and came up with this: https://stackoverflow.com/questions/18891472/monte-carlo-simulation-of-protein-structure-and-grid https://stackoverflow.com/questions/18891472/monte-carlo-sim...
- COGlory 6y ago
  This is last year's entry from Deep Mind: https://github.com/dellacortelab/prospr https://github.com/dellacortelab/prospr
werdnapk 6y ago
The Playstation 3 used to have Folding@Home that users could opt-in to. I've always thought that the cycles that crypto currencies burn for mining could be much better used for something like performing protein folding calculations (or something else beneficial) and mine some coin in the process.
- whoisterencelee 6y ago
  check Gridcoin.us
- AgentME 6y ago
  Algorithms used for proof-of-work have to produce solutions that are very efficient to verify (it needs to be much more efficient to verify than to compute, and it also just needs to be very efficient to verify overall because every potential block processed by each node has one), it needs to have a smoothly adjustable difficulty factor, and if the solutions are economically valuable to anyone, it weakens the value of it as a proof-of-work algorithm because it can cause mining to be a much less level playing field and cause double-spend attacks to be more profitable. Imagine a university gets a huge grant to run protein folding calculations, and the grant lets them do more than everyone else including miners: now they own >50% of the mining power of the cryptocurrency without making any investments intended toward mining and can now do 51% attacks at no added cost. Or imagine someone with less than 50% of the mining power trying to do a double-spend attack: normally this is discouraged by the fact that double-spend attacks are probabilistic, and the attacker has to pay the full cost for doing the attack regardless of whether it's successful. But if the proof-of-works are valuable outside of their purpose within cryptocurrency as proof-of-works, then the attacker can re-coup some of the costs of their attack by selling the results of their proof-of-works. Double-spend attacks will then have higher benefits and may be profitable to attempt now. Additionally, proof-of-work systems used by a decentralized cryptocurrency can't rely on a centrally-produced dataset. If the Folding@Home group produced workloads for the cryptocurrency miners to solve, then the group could construct fake workloads that they already knew the solutions to, and then secretly insta-mine those workloads themselves to earn mining fees or to do double-spend attacks on the network. I think it's better for cryptocurrencies to instead focus on developing solutions that just don't need proof-of-work mining to happen at all, like proof-of-stake.
jcims 6y ago
Apologies if I spam this stuff too much but I'm so intrigued by the dynamic complexity of this whole thing. The following three videos describe the process of DNA Transcription (copying a single gene's worth of RNA from the DNA strand), Translation (subject of TFA, creation of the protein from that RNA), and Replication (the process of making a complete copy of DNA for purposes of cell division. Keep in mind that the functional components you see in here are themselves (generally) proteins that are created (and have evolved) by a similar process. Transcription - https://www.youtube.com/watch?v=SMtWvDbfHLo https://www.youtube.com/watch?v=SMtWvDbfHLo Translation - https://www.youtube.com/watch?v=TfYf_rPWUdY https://www.youtube.com/watch?v=TfYf_rPWUdY Replication - https://www.youtube.com/watch?v=I9ArIJWYZHI https://www.youtube.com/watch?v=I9ArIJWYZHI
- koeng 6y ago
  If you want to have your mind blown even more, remember that all of these molecules are compressed in a super tight space (not a lot of space around them). Here is what a small bacteria would actually look like (artist rendition of course) https://cdn.rcsb.org/pdb101/goodsell/png-800/mycoplasma-mycoides.png https://cdn.rcsb.org/pdb101/goodsell/png-800/mycoplasma-myco...
  - airstrike 6y ago
    Really need this in higher res! My go-to mind-blowing visualization is this incredible video: https://vimeo.com/260291601/505c3bfec8 https://vimeo.com/260291601/505c3bfec8
    - tiborsaas 6y ago
      Thanks for this this was as creepy as amazing.
    - bitcharmer 6y ago
      Great video, but without any comments and the very few captions it's quite impossible to understand what's going on. Is there a version with a commentary or some richer description?
est 6y ago
One thing the article didn't mention is what else is untouched by AlphaFold in protein folding? I've read somewhere that dynamic folding is still unsolved?
- marktangotango 6y ago
  I think I read somewhere that the water molecules are thought form semi crystalline structures from protein surface charges that contribute to their function; you could imagine these forming channels or some other mechanism to orchestrate the liquid around the protein to aid it's function (so it's not all random molecules bumping into the spots it needs to go). I have no references for this though.
  - jcims 6y ago
    Ooh that’s wild, like a slippery elastic coating to guide interactions. If you’ve ever touched ferromagnetic fluid under the influence of a magnetic field, that’s how I’m imagining it.
- timr 6y ago
  Essentially all of it. Alphafold won't tell you anything about protein dynamics, side-chain positions, water interactions, charges, binding pockets or induced conformational changes. All of these things matter as much or more than the structure of the backbone itself. One way to think about it is this: alphafold gives you the rough shape of the skeleton, but a protein, just a like a human, has a lot more going on than just the skeleton.
  - s1artibartfast 6y ago
    I think at least some of this can be solved for or inferred from the final shape once it is known.
    - timr 6y ago
      Surprisingly little. Maybe things like binding pockets and broad classes of movement (hinges, etc.) can be inferred (sometimes). Otherwise, it's the other way around: the shape of the backbone is determined by the detailed interactions. Just think about alpha helices and beta sheets -- they're stabilized by hydrogen bonding patterns along the protein backbone, but the propensity of a particular residue to form a helix or a sheet is determined by interactions amongst the side-chain atoms in a particular context. The atomic interactions are the story, and the "fold" is really just the outline. Also, of course, it's not just the atoms in the protein itself: add in water, ions, small molecules, other proteins, etc., and you have a real mess. A small molecule (say, a drug), can displace a water molecule, which has a cost, which causes something else to move a bit to compensate, stretching a bond, and so on and so forth, sometimes resulting in dramatic differences in the bound conformation of a protein. It's not uncommon -- it's essentially the norm. And it's not like there's just one conformation. The whole thing is really like a wiggly, jiggly, metastable mass, and the introduction of a slight perturbation is enough to send the blob spiraling into a new metastable state. When you start to ask questions about how a protein moves over time, it becomes a much more complicated problem than predicting the overall conformation. Which is itself quite hard.
deleted 6y ago
[deleted]
victor106 6y ago
> Proteins are long chains of amino acids. Your DNA encodes these sequences, and RNA helps manufacture proteins according to this genetic blueprint. What does it mean when it says “Your DNA encodes these sequences”?
- analog31 6y ago
  DNA is like the source code for protein. That's its function. Specific triplets of bases along the chain correspond to specific amino acids, so a DNA strand ultimately results in production of a specific protein molecule. In turn, protein molecules do most of the specialized work in a cell, including controlling the intake and expulsion of small non-protein molecules from the surrounding medium. In turn, it's mainly the shape of protein molecules that makes them behave differently. And some proteins change shape under changing conditions within the cell, thus being able to function in a regulatory fashion.
  - lysp 6y ago
    Based on the animation above - basically a punch-card system.
- nabla9 6y ago
  Cool video that explains how RNA is used to make protein. https://dnalc.cshl.edu/view/15501-Translation-RNA-to-protein-3D-animation-with-basic-narration.html https://dnalc.cshl.edu/view/15501-Translation-RNA-to-protein...
- dilyevsky 6y ago
  Animated explanation - https://youtu.be/5MfSYnItYvg https://youtu.be/5MfSYnItYvg
- COGlory 6y ago
  Maybe I can explain this in computer terms. Think of DNA as read-only. It's a series of molecules that represent data. Cells read the topology and molecular interactions of those molecules and determine information from them. Now, because the DNA is read-only, the permissions are super restrictive. Which means if you want to access that data in the DNA, you need to go through an intermediate, which, when it leaves the restricted area, is ok if it gets destroyed, because that original copy is still intact. That's where RNA comes in. RNA is designed to be mutable and temporary. I think of it like system memory. Reboot the system, and you lose it all. Want to protect it? Write it to the disk (DNA)., Similarly, you don't mess with files right on the disk - first you read them to memory. So, RNA is basically DNA that's been read to memory, and can now be messed with. You can do something like execute it, which would be analogous to translating it to proteins. The process is similar. While 0s and 1s might translate to microcode calls (i.e. physical action on part of the computer sending electrons around), RNA translates to amino acids, the building blocks of proteins, which are the physical components of cells, and do things like...well...move electrons around, among other things. The way this works is that while 1010010101110 (I have no idea) might be some microcode call like OR or NOR, RNA bases (which are derived from the transcribed DNA) might say things like AUG, which tells the cell "OK go get the Methionine amino acid" or UUU which means "ok go get the phenylalanine amino acid". Chain enough amino acids together, and you get a protein, which essentially is a function in the cell. For instance, a protein of a specific sequence of amino acids might go fight off viruses. A protein of a different, but still specific sequence, might go produce energy.
eliben 6y ago
Could someone ELI5 why proteins fold in a unique way? Why can't there be multiple "valid" ways for them to fold (ignoring mirror symmetries)?
- jasoncrawford 6y ago
  Well, there are. Actually, misfolded proteins are implicated in some diseases. I'm not sure if every possible sequence of amino acids has a unique dominant folding. But ones that don't, wouldn't be nearly as useful biologically, because you couldn't rely on them to do their jobs. So they would not be selected for. The ones that actually get coded for by genes fold up more consistently.
  - rytill 6y ago
    > because you couldn't rely on them to do their jobs. So they would not be selected for. Wouldn't a 20% chance of a novel, useful interaction and 80% chance of no effect be almost as good if you are producing a lot of them?
    - COGlory 6y ago
      There are a few things in here that are fun to think about. In the situation you describe, the answer is often "yes" and that's how you end up with evolution. Let's say you have a gene that makes a protein that digests glucose. And then one day, your cell messed up when replicating and accidentally made an extra copy of that gene. Well now you have an extra copy of that gene that isn't under purifying selection. It's redundant. It can mutate but as long as you have the first copy, you're ok. And eventually it mutates away from being good at digesting glucose. It can do it a little bit, but it's not great. Maybe it's 20% as effective as it originally was. But you have another gene that's still 100% effective so you don't even notice. Now we have a protein that really doesn't do anything bad... It just doesn't do much good either. And since it isn't subject to purifying selection, every round of replication it keeps mutating. Until all of a sudden, it mutates into something that can digest lactose. Now, you have an evolutionary advantage from a protein that first had to get bad at binding glucose, before it could benefit you. But evolution has no foresight, so it didn't know. So it took getting rid of purifying selection to make it happen. But now as you come to rely on lactose, that protein will wind up back under purifying selection and become "fixed". So now let's consider an alternative situation. You only have one gene that can digest glucose. If it mutates to be 20% effective, you will at best grow only 20% as fast as your competitors. Maybe you even die and become an evolutionary dead end. In that case, it is an extreme disadvantage to have a protein that can't do its job reliably, and organisms that don't have a malfunctioning variant will grow better and pass on their genetic material to more offspring, until you are eventually outcompeted and go extinct. We can also imagine another scenario. Your glucose digesting protein mutates into something that can still bind glucose, but cant digest it. Then the glucose remains stuck to the protein, producing no energy, and becomes a waste for the cell. That is actively harmful and will likely kill the cell very quickly. So to answer your question: it depends
sandGorgon 6y ago
Quick question on Alphafold - is it a one time effort ? Like human genome sequencing. Like if we 3d map all the 170 million sequences (using alphafold or whatever),we are done right ? We can just look up in the library. New protein sequences don't continually get created ?
- jasoncrawford 6y ago
  Well, there's genetic engineering. We might want to create new proteins—enzymes for chemical reactions, for instance.
- cdirkx 6y ago
  From my understanding it was mostly useful for understanding new sequences in medical and genetic engineering; questions like can we modify this part of the protein and keep the overall structure the same.
- hobofan 6y ago
  > Like human genome sequencing Human genome sequencing was not a one time effort. The Human Genome Project was a one time push to establish the capabilities of human genome sequencing, but the field has seen a lot of refinement since then, to apply it both to individuals and to construct a better human reference genome. > New protein sequences don't continually get created? As others have said, there are new proteins being engineered by humans. Apart from that there are a lot of organisms that haven't been sequenced yet (not even counting niche organisms that haven't been discovered yet). Especially in the plant world, sequencing advancements with nanopore sequencing only recently made it economical (and possible) to sequence a lot of the plant genomes that are many times larger than the human one. So Alphafold might be comparable to the Human Genome Project in specific ways.
pdm55 6y ago
>> "DeepMind seems to be calling the protein folding problem solved, which strikes me as simplistic". I have a couple of questions, which might be related (1) Why did you call it out as "simplistic"? (2) Will the DeepMind team have to throw the same amount of computer power at each structure they seek to solve?
- jasoncrawford 6y ago
  (1) Simplistic because it isn't binary, solved vs. not solved. There's still improvement to do in the solution. And we won't really know if it's “solved” until we start trying to use these structures for practical purposes. Don't mean to detract from the accomplishment overall though, it seems tremendous. (2) There is a certain amount of computing needed for each new protein---quite significant, I think, but not prohibitively expensive. And I'm sure this can be improved over time
awongh 6y ago
Slightly tangential, but does anyone have recommendations for pop sci books on modern genetics / epigenetics? (Not specifically molecular cell biology/biochemistry).
- hgh 6y ago
  I enjoyed The Gene by Siddhartha Mukherjee. Depending on what you're looking for it might be relatively light on the science side and includes autobiographical digressions, but overall gives a high-level overview of key developments in the field. https://en.wikipedia.org/wiki/The_Gene:_An_Intimate_History https://en.wikipedia.org/wiki/The_Gene:_An_Intimate_History
imvetri 6y ago
https://vimeo.com/485900573 https://vimeo.com/485900573
BrandiATMuhkuh 6y ago
I worked besides my wife on some protein folding problems. People often want to know why it is so expensive. I unusual describe it as, someone gives you all Lego pieces in a Lego box. The job of the folding algorithm is, to re-create what's on the picture of the package without looking. I think it's easy to see, even if you only had 2 Lego bricks, that you have quite a lot of option to put the 2 bricks together. That grows quickly the more bricks you have.
k__ 6y ago
If a protein is a self assembling nano machine, why do we have to fold them manually in simulations?
- el_oni 6y ago
  That's a solid question. We know the sequence of amino acids, we know what order they are in. but remember they are assembled 1 at a time inside the cell. Andso the way they fold 1 at a time is different from simulating how the whole thing end-to-end will fold. another thing to be aware of is the environment in which it folds, the local pH can affect which -OH groups exist as OH or as O(minus), which affects the way it folds. Then there is local salt concentrations, various proteins incorperate calcium, magnesium or other metals into the structure. There are Post-translational modifications that are made, where other enzymes come in and snip bits off, add sugars to proteins, catalyse S-S bonds etc. Finally, we want to know how they are folded because we want to be able to modify their behavior. If you know that an enzyme is key in a disease you might want to design a drug molecule that can fit into its active site, for that we need to know how the protein is folded.
  - el_oni 6y ago
    Other ways to determine the way they are folded is to isolate the enzyme and to crystalise it and scatter Xrays through it. This is no mean feat, it takes a lot of time and a certain instinct (or brute force with a matrix of conditions) to pull off. Even if you manage to crystalise the protein, you need to check that it still performs the same function, otherwise you won't be getting the active structure. More recently NMR has been used, which gives information about the environment that the various nuclei occupy, and what their neighbors are. This has become more sophisticated over the last few years but only accounts for a small percentage of solved structures on the protein databank [0] [0] https://www.rcsb.org/ https://www.rcsb.org/
ptero 6y ago
Very well written overview of the problem and the solution approach for a non-biologist. Thank you!

314 points by jasoncrawford 6y ago

This is the TLDR from the article of the answer to the question "What is protein folding?": If a protein is essentially a self-assembling nanomachine, then the main purpose of the amino acid sequence is to produce the unique shape, charge distribution, etc. that determines the protein’s function. The article goes on to talk about other things, like "What if, instead of measuring a protein’s structure, we could predict it?" and that's cool, but it's sort of outside of the scope of the question posed in the title. I only kind of skimmed that section because it's about this project that is trying to figure out how to predict what shapes proteins fold into. Nifty tech, but not something I care a whole lot about. (Edit: If that tech interests you, there's also this on HN today: https://news.ycombinator.com/item?id=25253488 https://news.ycombinator.com/item?id=25253488 and I imagine that's why this was even posted -- because some people are probably wondering "What's a 101 explanation of protein folding?") Not covered by the article: Misfolded proteins are the crux of the problem with most genetic disorders. Your body produces this string of protein sequences and it fails to fold up into the unique shape that makes it a useful tool that does a specific job. (I always think of some old cartoon where two kids are playing with "gender neutral spiffy spiffy high minded description" toy from Switzerland -- think LEGOS only blocks you string together and bend as you see fit -- and their two mothers are talking and then one of the kids folds the bendable blocks into the shape of a gun and says "Bang" and one of the moms is all "Never mind.") Chemical derangement of the cell can interfere with protein folding. You have these little factories inside the cell that produce protein strings and as they come out, if the climate is chemically deranged (usually pH balance or salt imbalance are the culprits), then it won't fold. It just lays there, a stringy useless mess of protein. When you cook an egg, the egg white turns white and solidifies due to proteins being denatured. Denatured means they got unfolded. Sometimes when a protein is denatured -- unfolded -- it's reversible. Sometimes -- like with egg whites -- it's not. So in some cases if you could figure out why the protein is failing to fold properly, the body can potentially re-use denatured proteins and turn them back into working nanomachines. And sometimes it can't and then it has to go to some kind of garbage chute in the cell and some serious genetic disorders involve a failed garbage chute, so misfolds can't be effectively removed from the cell, which is a really huge problem. The "garbage chute" is some thing that basically digests the proteins.

deepfates 6y ago
thank you
flobosg 6y ago
You raise very good points about the role of protein folding and quality control in disease. But folding by itself is essentially a physicochemical process. A protein will fold (or its mutant will misfold) within a cell just like it would do it in a test tube. Don't underestimate the role of structure prediction in human disease. There are proteins known to be involved in disorders where a structure has been impossible to determine by experimental methods (membrane proteins are a known example). And there are still plenty of barely characterized proteins where a structural model might shed light on their function. > Your body produces this string of protein sequences A small nitpick: you meant "string of amino acids". In other words, a protein sequence. > Sometimes -- like with egg whites -- it's not. Under the right conditions even proteins in coagulated egg white can be renatured.
- DoreenMichele 6y ago
  TIL: Under the right conditions even proteins in coagulated egg white can be renatured. A small nitpick: you meant "string of amino acids". In other words, a protein sequence Thank you. You are correct. Don't underestimate the role of structure prediction in human disease. I'm not. I just don't really find the tech behind it fascinating. When they start coming out with articles saying "This project has successfully predicted X and this is clinically useful in this way," I'm sure I will read it on the edge of my seat like a gripping thriller.
  - COGlory 6y ago
    It's going to take quite some time until this gets accepted at the same level of experimental data, if ever.
    - DoreenMichele 6y ago
      I honestly have no idea what your point is.

whoisjuan 6y ago

That was an awesome explanation of this concept. I wish more complex concepts were explained with so much clarity and concision.

dukeofdoom 6y ago

Is there a simple python example, with protein Data and an Algorithm to fold it.

DoreenMichele 6y ago
I don't actually know. I'm just futzing around online while unable to get to sleep. But I googled "python play with protein folding" and came up with this: https://stackoverflow.com/questions/18891472/monte-carlo-simulation-of-protein-structure-and-grid https://stackoverflow.com/questions/18891472/monte-carlo-sim...
COGlory 6y ago
This is last year's entry from Deep Mind: https://github.com/dellacortelab/prospr https://github.com/dellacortelab/prospr

werdnapk 6y ago

The Playstation 3 used to have Folding@Home that users could opt-in to. I've always thought that the cycles that crypto currencies burn for mining could be much better used for something like performing protein folding calculations (or something else beneficial) and mine some coin in the process.

whoisterencelee 6y ago
check Gridcoin.us
AgentME 6y ago
Algorithms used for proof-of-work have to produce solutions that are very efficient to verify (it needs to be much more efficient to verify than to compute, and it also just needs to be very efficient to verify overall because every potential block processed by each node has one), it needs to have a smoothly adjustable difficulty factor, and if the solutions are economically valuable to anyone, it weakens the value of it as a proof-of-work algorithm because it can cause mining to be a much less level playing field and cause double-spend attacks to be more profitable. Imagine a university gets a huge grant to run protein folding calculations, and the grant lets them do more than everyone else including miners: now they own >50% of the mining power of the cryptocurrency without making any investments intended toward mining and can now do 51% attacks at no added cost. Or imagine someone with less than 50% of the mining power trying to do a double-spend attack: normally this is discouraged by the fact that double-spend attacks are probabilistic, and the attacker has to pay the full cost for doing the attack regardless of whether it's successful. But if the proof-of-works are valuable outside of their purpose within cryptocurrency as proof-of-works, then the attacker can re-coup some of the costs of their attack by selling the results of their proof-of-works. Double-spend attacks will then have higher benefits and may be profitable to attempt now. Additionally, proof-of-work systems used by a decentralized cryptocurrency can't rely on a centrally-produced dataset. If the Folding@Home group produced workloads for the cryptocurrency miners to solve, then the group could construct fake workloads that they already knew the solutions to, and then secretly insta-mine those workloads themselves to earn mining fees or to do double-spend attacks on the network. I think it's better for cryptocurrencies to instead focus on developing solutions that just don't need proof-of-work mining to happen at all, like proof-of-stake.

jcims 6y ago

Apologies if I spam this stuff too much but I'm so intrigued by the dynamic complexity of this whole thing. The following three videos describe the process of DNA Transcription (copying a single gene's worth of RNA from the DNA strand), Translation (subject of TFA, creation of the protein from that RNA), and Replication (the process of making a complete copy of DNA for purposes of cell division. Keep in mind that the functional components you see in here are themselves (generally) proteins that are created (and have evolved) by a similar process. Transcription - https://www.youtube.com/watch?v=SMtWvDbfHLo https://www.youtube.com/watch?v=SMtWvDbfHLo Translation - https://www.youtube.com/watch?v=TfYf_rPWUdY https://www.youtube.com/watch?v=TfYf_rPWUdY Replication - https://www.youtube.com/watch?v=I9ArIJWYZHI https://www.youtube.com/watch?v=I9ArIJWYZHI

koeng 6y ago
If you want to have your mind blown even more, remember that all of these molecules are compressed in a super tight space (not a lot of space around them). Here is what a small bacteria would actually look like (artist rendition of course) https://cdn.rcsb.org/pdb101/goodsell/png-800/mycoplasma-mycoides.png https://cdn.rcsb.org/pdb101/goodsell/png-800/mycoplasma-myco...
- airstrike 6y ago
  Really need this in higher res! My go-to mind-blowing visualization is this incredible video: https://vimeo.com/260291601/505c3bfec8 https://vimeo.com/260291601/505c3bfec8
  - tiborsaas 6y ago
    Thanks for this this was as creepy as amazing.
  - bitcharmer 6y ago
    Great video, but without any comments and the very few captions it's quite impossible to understand what's going on. Is there a version with a commentary or some richer description?

est 6y ago

One thing the article didn't mention is what else is untouched by AlphaFold in protein folding? I've read somewhere that dynamic folding is still unsolved?

marktangotango 6y ago
I think I read somewhere that the water molecules are thought form semi crystalline structures from protein surface charges that contribute to their function; you could imagine these forming channels or some other mechanism to orchestrate the liquid around the protein to aid it's function (so it's not all random molecules bumping into the spots it needs to go). I have no references for this though.
- jcims 6y ago
  Ooh that’s wild, like a slippery elastic coating to guide interactions. If you’ve ever touched ferromagnetic fluid under the influence of a magnetic field, that’s how I’m imagining it.
timr 6y ago
Essentially all of it. Alphafold won't tell you anything about protein dynamics, side-chain positions, water interactions, charges, binding pockets or induced conformational changes. All of these things matter as much or more than the structure of the backbone itself. One way to think about it is this: alphafold gives you the rough shape of the skeleton, but a protein, just a like a human, has a lot more going on than just the skeleton.
- s1artibartfast 6y ago
  I think at least some of this can be solved for or inferred from the final shape once it is known.
  - timr 6y ago
    Surprisingly little. Maybe things like binding pockets and broad classes of movement (hinges, etc.) can be inferred (sometimes). Otherwise, it's the other way around: the shape of the backbone is determined by the detailed interactions. Just think about alpha helices and beta sheets -- they're stabilized by hydrogen bonding patterns along the protein backbone, but the propensity of a particular residue to form a helix or a sheet is determined by interactions amongst the side-chain atoms in a particular context. The atomic interactions are the story, and the "fold" is really just the outline. Also, of course, it's not just the atoms in the protein itself: add in water, ions, small molecules, other proteins, etc., and you have a real mess. A small molecule (say, a drug), can displace a water molecule, which has a cost, which causes something else to move a bit to compensate, stretching a bond, and so on and so forth, sometimes resulting in dramatic differences in the bound conformation of a protein. It's not uncommon -- it's essentially the norm. And it's not like there's just one conformation. The whole thing is really like a wiggly, jiggly, metastable mass, and the introduction of a slight perturbation is enough to send the blob spiraling into a new metastable state. When you start to ask questions about how a protein moves over time, it becomes a much more complicated problem than predicting the overall conformation. Which is itself quite hard.

deleted 6y ago

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victor106 6y ago

> Proteins are long chains of amino acids. Your DNA encodes these sequences, and RNA helps manufacture proteins according to this genetic blueprint. What does it mean when it says “Your DNA encodes these sequences”?

analog31 6y ago
DNA is like the source code for protein. That's its function. Specific triplets of bases along the chain correspond to specific amino acids, so a DNA strand ultimately results in production of a specific protein molecule. In turn, protein molecules do most of the specialized work in a cell, including controlling the intake and expulsion of small non-protein molecules from the surrounding medium. In turn, it's mainly the shape of protein molecules that makes them behave differently. And some proteins change shape under changing conditions within the cell, thus being able to function in a regulatory fashion.
- lysp 6y ago
  Based on the animation above - basically a punch-card system.
nabla9 6y ago
Cool video that explains how RNA is used to make protein. https://dnalc.cshl.edu/view/15501-Translation-RNA-to-protein-3D-animation-with-basic-narration.html https://dnalc.cshl.edu/view/15501-Translation-RNA-to-protein...
dilyevsky 6y ago
Animated explanation - https://youtu.be/5MfSYnItYvg https://youtu.be/5MfSYnItYvg
COGlory 6y ago
Maybe I can explain this in computer terms. Think of DNA as read-only. It's a series of molecules that represent data. Cells read the topology and molecular interactions of those molecules and determine information from them. Now, because the DNA is read-only, the permissions are super restrictive. Which means if you want to access that data in the DNA, you need to go through an intermediate, which, when it leaves the restricted area, is ok if it gets destroyed, because that original copy is still intact. That's where RNA comes in. RNA is designed to be mutable and temporary. I think of it like system memory. Reboot the system, and you lose it all. Want to protect it? Write it to the disk (DNA)., Similarly, you don't mess with files right on the disk - first you read them to memory. So, RNA is basically DNA that's been read to memory, and can now be messed with. You can do something like execute it, which would be analogous to translating it to proteins. The process is similar. While 0s and 1s might translate to microcode calls (i.e. physical action on part of the computer sending electrons around), RNA translates to amino acids, the building blocks of proteins, which are the physical components of cells, and do things like...well...move electrons around, among other things. The way this works is that while 1010010101110 (I have no idea) might be some microcode call like OR or NOR, RNA bases (which are derived from the transcribed DNA) might say things like AUG, which tells the cell "OK go get the Methionine amino acid" or UUU which means "ok go get the phenylalanine amino acid". Chain enough amino acids together, and you get a protein, which essentially is a function in the cell. For instance, a protein of a specific sequence of amino acids might go fight off viruses. A protein of a different, but still specific sequence, might go produce energy.

eliben 6y ago

Could someone ELI5 why proteins fold in a unique way? Why can't there be multiple "valid" ways for them to fold (ignoring mirror symmetries)?

jasoncrawford 6y ago
Well, there are. Actually, misfolded proteins are implicated in some diseases. I'm not sure if every possible sequence of amino acids has a unique dominant folding. But ones that don't, wouldn't be nearly as useful biologically, because you couldn't rely on them to do their jobs. So they would not be selected for. The ones that actually get coded for by genes fold up more consistently.
- rytill 6y ago
  > because you couldn't rely on them to do their jobs. So they would not be selected for. Wouldn't a 20% chance of a novel, useful interaction and 80% chance of no effect be almost as good if you are producing a lot of them?
  - COGlory 6y ago
    There are a few things in here that are fun to think about. In the situation you describe, the answer is often "yes" and that's how you end up with evolution. Let's say you have a gene that makes a protein that digests glucose. And then one day, your cell messed up when replicating and accidentally made an extra copy of that gene. Well now you have an extra copy of that gene that isn't under purifying selection. It's redundant. It can mutate but as long as you have the first copy, you're ok. And eventually it mutates away from being good at digesting glucose. It can do it a little bit, but it's not great. Maybe it's 20% as effective as it originally was. But you have another gene that's still 100% effective so you don't even notice. Now we have a protein that really doesn't do anything bad... It just doesn't do much good either. And since it isn't subject to purifying selection, every round of replication it keeps mutating. Until all of a sudden, it mutates into something that can digest lactose. Now, you have an evolutionary advantage from a protein that first had to get bad at binding glucose, before it could benefit you. But evolution has no foresight, so it didn't know. So it took getting rid of purifying selection to make it happen. But now as you come to rely on lactose, that protein will wind up back under purifying selection and become "fixed". So now let's consider an alternative situation. You only have one gene that can digest glucose. If it mutates to be 20% effective, you will at best grow only 20% as fast as your competitors. Maybe you even die and become an evolutionary dead end. In that case, it is an extreme disadvantage to have a protein that can't do its job reliably, and organisms that don't have a malfunctioning variant will grow better and pass on their genetic material to more offspring, until you are eventually outcompeted and go extinct. We can also imagine another scenario. Your glucose digesting protein mutates into something that can still bind glucose, but cant digest it. Then the glucose remains stuck to the protein, producing no energy, and becomes a waste for the cell. That is actively harmful and will likely kill the cell very quickly. So to answer your question: it depends

sandGorgon 6y ago

Quick question on Alphafold - is it a one time effort ? Like human genome sequencing. Like if we 3d map all the 170 million sequences (using alphafold or whatever),we are done right ? We can just look up in the library. New protein sequences don't continually get created ?

jasoncrawford 6y ago
Well, there's genetic engineering. We might want to create new proteins—enzymes for chemical reactions, for instance.
cdirkx 6y ago
From my understanding it was mostly useful for understanding new sequences in medical and genetic engineering; questions like can we modify this part of the protein and keep the overall structure the same.
hobofan 6y ago
> Like human genome sequencing Human genome sequencing was not a one time effort. The Human Genome Project was a one time push to establish the capabilities of human genome sequencing, but the field has seen a lot of refinement since then, to apply it both to individuals and to construct a better human reference genome. > New protein sequences don't continually get created? As others have said, there are new proteins being engineered by humans. Apart from that there are a lot of organisms that haven't been sequenced yet (not even counting niche organisms that haven't been discovered yet). Especially in the plant world, sequencing advancements with nanopore sequencing only recently made it economical (and possible) to sequence a lot of the plant genomes that are many times larger than the human one. So Alphafold might be comparable to the Human Genome Project in specific ways.

pdm55 6y ago

>> "DeepMind seems to be calling the protein folding problem solved, which strikes me as simplistic". I have a couple of questions, which might be related (1) Why did you call it out as "simplistic"? (2) Will the DeepMind team have to throw the same amount of computer power at each structure they seek to solve?

jasoncrawford 6y ago
(1) Simplistic because it isn't binary, solved vs. not solved. There's still improvement to do in the solution. And we won't really know if it's “solved” until we start trying to use these structures for practical purposes. Don't mean to detract from the accomplishment overall though, it seems tremendous. (2) There is a certain amount of computing needed for each new protein---quite significant, I think, but not prohibitively expensive. And I'm sure this can be improved over time

awongh 6y ago

Slightly tangential, but does anyone have recommendations for pop sci books on modern genetics / epigenetics? (Not specifically molecular cell biology/biochemistry).

hgh 6y ago
I enjoyed The Gene by Siddhartha Mukherjee. Depending on what you're looking for it might be relatively light on the science side and includes autobiographical digressions, but overall gives a high-level overview of key developments in the field. https://en.wikipedia.org/wiki/The_Gene:_An_Intimate_History https://en.wikipedia.org/wiki/The_Gene:_An_Intimate_History

imvetri 6y ago

https://vimeo.com/485900573 https://vimeo.com/485900573

BrandiATMuhkuh 6y ago

I worked besides my wife on some protein folding problems. People often want to know why it is so expensive. I unusual describe it as, someone gives you all Lego pieces in a Lego box. The job of the folding algorithm is, to re-create what's on the picture of the package without looking. I think it's easy to see, even if you only had 2 Lego bricks, that you have quite a lot of option to put the 2 bricks together. That grows quickly the more bricks you have.

k__ 6y ago

If a protein is a self assembling nano machine, why do we have to fold them manually in simulations?

el_oni 6y ago
That's a solid question. We know the sequence of amino acids, we know what order they are in. but remember they are assembled 1 at a time inside the cell. Andso the way they fold 1 at a time is different from simulating how the whole thing end-to-end will fold. another thing to be aware of is the environment in which it folds, the local pH can affect which -OH groups exist as OH or as O(minus), which affects the way it folds. Then there is local salt concentrations, various proteins incorperate calcium, magnesium or other metals into the structure. There are Post-translational modifications that are made, where other enzymes come in and snip bits off, add sugars to proteins, catalyse S-S bonds etc. Finally, we want to know how they are folded because we want to be able to modify their behavior. If you know that an enzyme is key in a disease you might want to design a drug molecule that can fit into its active site, for that we need to know how the protein is folded.
- el_oni 6y ago
  Other ways to determine the way they are folded is to isolate the enzyme and to crystalise it and scatter Xrays through it. This is no mean feat, it takes a lot of time and a certain instinct (or brute force with a matrix of conditions) to pull off. Even if you manage to crystalise the protein, you need to check that it still performs the same function, otherwise you won't be getting the active structure. More recently NMR has been used, which gives information about the environment that the various nuclei occupy, and what their neighbors are. This has become more sophisticated over the last few years but only accounts for a small percentage of solved structures on the protein databank [0] [0] https://www.rcsb.org/ https://www.rcsb.org/

ptero 6y ago

Very well written overview of the problem and the solution approach for a non-biologist. Thank you!