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.
Ugh...ok so not reliable to drive experimental follow ups it seems.
What would it cost to image a certain protein if I sent you the mutant cell lines roughly? I've got 4 mutants whose structure I'm interested in looking at. I can get into more details but essentially, what I'm trying to figure out is if a truncated version of this protein can be created that would expose all the right binding sites and maybe fold somewhat correctly in order to be delivery via AAV for gene therapy.
The mutants I want to look at aren't the truncated protein but the actual diseased types and if I saw structural problems in them, I might assume that fixing said structure could restore function.
“We could search for a new protein that matches the melody and rhythm of an antibody capable of binding to the spike protein, interfering with its ability to infect,” said Professor Buehler.
Interesting. Encode the info, in potentially, an easier format for comparison.
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
Yes, a crystallized protein will always be in a single conformation, or you won't be able to see it because the electron density map will be an average of all possible conformations, and therefore meaningless.
Single particle gives you the opportunity to see different conformations, but only if the data is discrete. If there's a continuous amount of conformations (think a molecular motor that's rotating) you would need nearly infinite data to resolve a nearly infinite number of conformations. If the data is less than continuous, you can image enough particles to see all the different conformations by constructing multiple models in parallel and using 3D angular searching to bin them by what conformation they are in. This is a computationally exhausting process, however.
If you're interested in a fairly long discussion with the(?!) guy who developed the stabilized spike protein substitutions. Have a look at this TWiV.
https://www.youtube.com/watch?v=P9S28_5AqUA
I'm not aware of any, but I don't think that until we're able to see proteins moving we'll actually be able to answer those questions visually. We've got a long way to go before that happens.
Hey Naveen, I know that there are some epitopes that can only be recognized if there's a weird domain swap that happens, causing antibodies to be "four-pronged" instead of "two pronged". I think it's a proline substitution in the conserved neck region. Did you screen out those epitopes from your ML?
Also good luck! I'm chipping in now. I'm relaunching my own crowd-funded nonprofit research in the biomedical space (and will be partnering with crowdhoster/crowdtilt)... I'm magnifying your message. When the dust settles a little bit I'd love to be in touch with you guys.
Who knows what kinds of selective pressure this section of the genome has been exposed to?
Probably none. You would be hard pressed to conjure up a reason to explain why a sequence that codes for a non-functional protein would be functionally conserved for 7 million years. (You could win a Nobel prize for such a revolutionary contribution.)
I work in drug design. Let me assure you that even a single mutation can render the structure of a protein completely inert.
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.
Neither the protein sequence nor structure spaces have been fully explored, and the sequence set of UniProt does not represent every single extant protein. My answer is “no”.
The “proteins of the same structure” we are talking about here are virus spike proteins. Assuming that there is a pathway that leads to the misfolded form propagating to begin with, the damage is that other spike proteins don’t work. These proteins, however, were never intended to perform any function whatsoever.
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.
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