[HN Gopher] More Protein Folding Progress - What's It Mean?
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More Protein Folding Progress - What's It Mean?
Author : pvsukale3
Score : 74 points
Date : 2021-07-26 17:26 UTC (5 hours ago)
(HTM) web link (blogs.sciencemag.org)
(TXT) w3m dump (blogs.sciencemag.org)
| joshtam wrote:
| AF2 certainly moves us forward, especially for proteins where no
| structure was previously available
| COGlory wrote:
| I am a structural biologist studying Archaeal viruses and
| CRISPR/Cas proteins. From my point of view, AlphaFold has
| basically just gotten better at multiple sequence alignments.
| It's not a bad thing, but it's unfortunate useless to me because
| sequence divergence happens so quickly in the organisms I study
| that even the best results are still basically made up. It's nice
| that AlphaFold got better at generating sequence alignments, but
| it's not a magic bullet (a la folding figured out from first
| principles.)
|
| Interestingly enough, if I get experimental data of an archeal
| virus protein, it almost always uses a conserved fold. There's
| just no evidence at the amino acid level.
| the__alchemist wrote:
| I agree. AlphaFold's approach isn't what I was hoping.
| Something ab initio would be ground-breaking. Especially if you
| could apply it to chemistry more broadly than protein folding.
| AlphaFold's approach seems like a recipe for over-fitting.
| Filligree wrote:
| I would be honestly surprised if a true simulation is
| possible that can also run on a classical (non-quantum)
| computer, but I've been surprised before.
|
| It would indeed be ground-breaking.
| dnautics wrote:
| One crazy idea I have is to run some very crude ab-initio
| QM or DFT stuff starting with folded proteins, and
| gradually running the temperature higher until it unfolds.
| Then amass a dataset of protein structures + positional
| delta vectors. Then time-reverse the dataset (flip the sign
| on those vectors). Then train a 3d convolutional NN on the
| reverse-melting curve to obtain heuristic rules for folding
| in whatever universe the shitty physics engine represents.
|
| Then it doesn't matter if the QM simulation is very crude
| and deeply flawed, so long as it gets to the right answer
| at the end.
| dekhn wrote:
| IIUC the folding and unfolding pathways of a protein are
| not time reversed wrt each other.
|
| But you would still enjoy reading this:
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC17732/ the
| work in this paper led to folding@home because vijay
| couldn't get enough computer time to run his simulations
|
| if you really had a lot of computer time to waste, you
| could imagine doing simulations where you titired in or
| out some guanadinum chloride and inspected how disrupting
| h-bonds (versus hydrophobic collapse) contributes.
| Chaotropes are better than temperature for probing
| unfolding.
| dekhn wrote:
| Check out DESMOND and ANTON, that's basically what DE Shaw
| Research is doing. It does seem like, to get static
| structure predictions, it's going to be hard for anybody to
| find anything that does marginally better than AF2 at this
| point, but since static structure predicitons are just
| mostly useful for brainstorming, I think ANTON may end up
| being more useful, in terms of applied science.
| eutectic wrote:
| I wonder if a transformer with 1 recurrent layer (or a
| transformer Deep Equilibrium Model) could work well.
| Transformers are almost like a physics simulation in that
| they sum vector-valued interactions which depend on
| distance in some space, and then add the result to the
| state of each particle / element.
| dekhn wrote:
| Reasonably speaking, I would expect that within 2 years
| 10 groups will be as proficient as AF2 at predicting
| static structures. I don't think anybody who is trying to
| emulate physics simulations will be in that group, just
| folks who have learned enough tricks to quickly
| incorporate all the evidence during training and choose
| how to apply it during prediction.
|
| I expect to see a "multiple feature embedding heads on
| top of 2 fullly connected layers" (as used in modern ads
| training) will end up being the simplest architecture
| capable of folding proteins well.
| isoprophlex wrote:
| One can dream about being able to calculate energies with the
| accuracy of DFT calculations... and do dynamic simulations on
| the time scale of ball-and-stick molecular modeling sims.
|
| Would be amazing for homogeneous catalysis design.
| ramraj07 wrote:
| Can you explain further what your second paragraph means?
| G3rn0ti wrote:
| I think parent meant conservation of the amino acid is weak
| and still the structure remains the same overall. So sequence
| similarity is not everything.
|
| Reason might be the overall protein fold is guided also by
| something else than detailed side chain contacts.
|
| BTW: Hydrogen bonding and salt contacts do not drive protein
| folding at least not thermodynamically because it does not
| matter whether polar/charged residues interact with others or
| with water. Rather, the reason why proteins fold is the same
| why oil and water do not mix: Hydrophobic amino acids avoid
| water. This is an entropy driven process where electrostatic
| interactions do not matter. See also the ,,molten globules"
| model. Basically it means a predecessor of the protein folds
| early on due to a collapse of the hydrophobic core. Tertiary
| structure is then refined due to residue/residue
| interactions. In the end, it's the distribution of
| hydrophobic amino acids in its sequence that's most important
| for the conservation of a structure. Surface residues can
| vary quite a lot.
| dekhn wrote:
| your "BTW" is still a huge area of argument in protein
| folding, the claim you are making is just one perspective
| and is not well-established.
| strbean wrote:
| I never considered that there would be viruses that infect
| Archaea. That sounds incredibly cool!
|
| Any fun tidbits about them you'd like to share?
| kleton wrote:
| There's a theory that the eukaryotic nucleus originated as an
| archaeal virus
| https://en.wikipedia.org/wiki/Viral_eukaryogenesis
| strbean wrote:
| That is super cool!
| jostmey wrote:
| How do you know the results are _basically made up_? Have you
| compared AlphaFold 's predictions to your experimental data.
|
| I think you are right that most of the predictive power derives
| from super-enhanced multiple sequence alignments, but I think
| you underestimate AlphaFold's ability to generalize to novel
| cases
| mrfusion wrote:
| Could people like you help to improve alphafold? Did they
| already train it on the proteins you work with?
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