3 ms·

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?

by est 6y ago

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.

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?

by 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.