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Question from a non-molecular-biologist: IIUC, when COVID first gained notoriety, there was a large public effort to solve its molecular structure [0]. Articl

Question from a non-molecular-biologist: IIUC, when COVID first gained notoriety, there was a large public effort to solve its molecular structure [0]. Articles like this seem to imply that they've solved the structure of numerous variants, making me think we (collectively) can do it much more quickly now. If that's really true, what's changed? Does knowing the structure of other COVID variants give us a massive head start? Or has there been a massive investment in computing power for solving COVID-variant stuctures? [0] https://foldingathome.org/diseases/infectious-diseases/covid-19/?lng=en-US https://foldingathome.org/diseases/infectious-diseases/covid...

timr 5y ago
No, there are not solved structures for these variants (in general). They're using computer modeling. Even if there were, changes of a single amino acid that don't induce significant conformational (shape) change are the sort of thing that you'd need a very good structure to discern, since they're mostly on the surface of the spike, and probably spin around a lot. The most relevant thing to know is what a mutation / mutations looks like in the context of antibody binding, but that's even harder to get a good structure. It's not something that can be done quickly.
- rolph 5y ago
  when the focus is on individual molecules it is about a statistical measure of bond angle, distance, resonanceforms, charge distribution, and rotational freedom. this ends up looking like the quantum physics conundrum where there is a central tendency rather than certainty, until you pin it down in some way. this is why we have a vaccine to begin with, the realization that there are conformational frequencies to the S protien, and a particular locus in the sequence is associated with the conformational change that sequesters the binding domain of S protien. thus the 2proline version of S was used in subsequent vaccines, allowing the ACE2 binding domain to remain exposed to the PAMP recognition machinery. it takes months or weeks depending on how well the supervising scientist receives a request, it used to take years and decades in many cases.
  - timr 5y ago
    > this ends up looking like the quantum physics conundrum where there is a central tendency rather than certainty, until you pin it down in some way. Yes, this is always true. Entropy is real, and loss of entropy affects free energy of binding. Even "structures" aren't really structures, but instantaneous pictures of a system in constant motion.
rolph 5y ago
yes to all. the early days of biochemistry were heavily dependent on x-ray crystallography, meaning the subject structure was in crystalline form, meaning there was a bias toward understanding of structures that facilitated crystalization. sequencing and structural studies[folding] were slow tedious wetlab efforts until mid 90s when computing power was of caliber, and shared across the internet, we now have such computation cheaper smaller, and locally. like any jigsaw puzzle, the more pieces correctly placed the easier it becomes to progress.
b9a2cab5 5y ago
Computational docking (figuring out what drug molecules bind strongly to) is still not solved. In order to find drugs that 1. work well and 2. aren't toxic we need robust docking estimators that work well over a wide variety of proteins. My understanding of the space (which comes from undergrad comp bio, so please someone feel free to correct me) is that just having a molecule that binds well to your target doesn't mean it's going to work well as a drug, because there are delivery and toxicity concerns.
- deleted 5y ago
  [deleted]
clairity 5y ago
at least for identifying variants, you don’t necessarily need to know the full (highly complex) structure of each variant, just the relevant diffs from the original variant, and computer modeling to tease out whether the diffs are significant enough to warrant a ‘variant’ label (along with epidemiological data, of course). once identified and labeled, pcr can give you enough information (via the differing prevalences of short sequences of dna/rna that act like unique fingerprints) to tell the variants apart without needing to know anything about the structure.
snowwrestler 5y ago
Famously, once the novel coronavirus was sequenced, Moderna had their mRNA sequence ready just a few days later. This was well-covered in the press. All the time from then to general availability of their vaccine was spent on testing and scaling. This is not exactly what you asked. But if the question is whether we have a speed advantage on vaccines because of greater understanding of viruses now, the answer is yes. It’s one reason the COVID-19 vaccine was the fastest in history. Should it become necessary to separately vaccinate against coronavirus variants, the same advantage would confer. And vaccine makers have said they are monitoring variants and ready to go, if necessary. The question is, will it be necessary? And how much testing will variant vaccines need to undergo?

timr 5y ago

No, there are not solved structures for these variants (in general). They're using computer modeling. Even if there were, changes of a single amino acid that don't induce significant conformational (shape) change are the sort of thing that you'd need a very good structure to discern, since they're mostly on the surface of the spike, and probably spin around a lot. The most relevant thing to know is what a mutation / mutations looks like in the context of antibody binding, but that's even harder to get a good structure. It's not something that can be done quickly.

rolph 5y ago
when the focus is on individual molecules it is about a statistical measure of bond angle, distance, resonanceforms, charge distribution, and rotational freedom. this ends up looking like the quantum physics conundrum where there is a central tendency rather than certainty, until you pin it down in some way. this is why we have a vaccine to begin with, the realization that there are conformational frequencies to the S protien, and a particular locus in the sequence is associated with the conformational change that sequesters the binding domain of S protien. thus the 2proline version of S was used in subsequent vaccines, allowing the ACE2 binding domain to remain exposed to the PAMP recognition machinery. it takes months or weeks depending on how well the supervising scientist receives a request, it used to take years and decades in many cases.
- timr 5y ago
  > this ends up looking like the quantum physics conundrum where there is a central tendency rather than certainty, until you pin it down in some way. Yes, this is always true. Entropy is real, and loss of entropy affects free energy of binding. Even "structures" aren't really structures, but instantaneous pictures of a system in constant motion.

rolph 5y ago

yes to all. the early days of biochemistry were heavily dependent on x-ray crystallography, meaning the subject structure was in crystalline form, meaning there was a bias toward understanding of structures that facilitated crystalization. sequencing and structural studies[folding] were slow tedious wetlab efforts until mid 90s when computing power was of caliber, and shared across the internet, we now have such computation cheaper smaller, and locally. like any jigsaw puzzle, the more pieces correctly placed the easier it becomes to progress.

b9a2cab5 5y ago

Computational docking (figuring out what drug molecules bind strongly to) is still not solved. In order to find drugs that 1. work well and 2. aren't toxic we need robust docking estimators that work well over a wide variety of proteins. My understanding of the space (which comes from undergrad comp bio, so please someone feel free to correct me) is that just having a molecule that binds well to your target doesn't mean it's going to work well as a drug, because there are delivery and toxicity concerns.

deleted 5y ago
[deleted]

clairity 5y ago

at least for identifying variants, you don’t necessarily need to know the full (highly complex) structure of each variant, just the relevant diffs from the original variant, and computer modeling to tease out whether the diffs are significant enough to warrant a ‘variant’ label (along with epidemiological data, of course). once identified and labeled, pcr can give you enough information (via the differing prevalences of short sequences of dna/rna that act like unique fingerprints) to tell the variants apart without needing to know anything about the structure.

snowwrestler 5y ago

Famously, once the novel coronavirus was sequenced, Moderna had their mRNA sequence ready just a few days later. This was well-covered in the press. All the time from then to general availability of their vaccine was spent on testing and scaling. This is not exactly what you asked. But if the question is whether we have a speed advantage on vaccines because of greater understanding of viruses now, the answer is yes. It’s one reason the COVID-19 vaccine was the fastest in history. Should it become necessary to separately vaccinate against coronavirus variants, the same advantage would confer. And vaccine makers have said they are monitoring variants and ready to go, if necessary. The question is, will it be necessary? And how much testing will variant vaccines need to undergo?