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Just for fun I looked at the Omicron mutations.

Disclaimer: to really analyze this sucker, I’d have to have access to some papers on the structure of the spike protein as well as a app that allows me to do protein visualizations and graphics. I have an old MacBook that Apple lovingly calls “legacy” and I have a very basic old application that does, well, very basic applicationy things. It’s been about 4 years since I’ve done it but I used to love looking at protein structures so if anyone is interested in seeing what I see, let me know and I’ll spend a couple of hours making some pretty pictures.

With that out of the way, this is my first *blink* impression of the omicron variant mutations on structure based exclusively on the sequence changes. I’m not mapping them on the structure. (By the way, the European site, Swiss Model, has already posted some models where the mutations are mapped on a crystal structure but I don’t really like the display they’re using. I’d prefer one that allowed me to play with surfaces, look at backbone changes and amino acid interactions. I can’t really do that to my satisfaction on a fiddly little 3D model. Yes, I was spoiled)

Omicron is pretty F#%^ing weird.

Let’s start with a well known thing about proteins. The stabilizing forces that keep them together are only slightly greater than the destabilizing forces that tear them apart. To maintain the right “fold” and behave in the same way, a protein can’t make too many substitutions. One or two critical mutations or insertions/deletions can have the capacity to substantially change a protein’s activity. In the case of omicron, there are 32 changes. Some of those changes are conservative. In other words, the amino acid change is of the same type. Conservative changes usually don’t destabilize proteins if the interactions remain the same overall.

But with omicron, there are some pretty important, non-conservative changes. For example, there are 4 glycine mutations. Glycine is the smallest amino acid and it’s important because it makes protein strands flexible where they are located. By changing 4 glycines to something else the protein may be less able to change its shape with respect to its target or its own structure. I’m used to seeing glycines in sections of proteins that have interactions in the binding sites. The protein accommodates the target by rippling and rolling where the glycines are. Imagine sticking a big irregular chunk of ice in a silicone mold versus a metal muffin tin. You have more flex in the silicone. It’s more forgiving. Losing those three glycines means there’s less give, like a metal muffin tin.

There is one mutation that gains a glycine but the overall effect is a net loss of 3 glycines. The importance of these losses depends on where they are located. That’s why I need the papers and the app. And the new MacBook Pro. 🤙 Apple.

There are also three deletion sites. One of those deletion sites occurs adjacent to the loss of one of those glycines. In fact, that site deletes three amino acids. So, you have the loss of a floppy amino acid substituted with an acidic amino acid followed by the loss of three amino acids. Sounds like it could be important. That section of protein is going to be shorter and less flexible. I just noticed that delta also has a glycine to aspartic acid mutation at the same spot but it doesn’t have the following three deletions. Also, delta doesn’t lose any other glycines. So, it’s wigglier than omicron.

There is a loss of a proline, which causes kinks in a protein chain, and a gain of a proline somewhere else. It’s a net of zero but location, location, location. There’s also a weird insertion where the insertion that looks like a gain of three amino acids with a proline kink in the second position.

There are 9 mutations where the amino acid becomes more basic. Most of them are from asparagine to lysine. It’s not highly conserved but I can see why the protein might allow for this substitution. Im guessing that it doesn’t have much of a structural impact but it might affect the potency of the vaccines. Some other notable changes are a loss of a few serines for more greasy amino acids. That could have an effect on structure and antibody or T-cell recognition. Again, location is key. If it does affect recognition, it’s something that can be fixed pretty quickly with a new mRNA vaccine.

So, anyway, there you have my quick peek at omicron. Maybe not as infectious as delta but more likely to be an escape variant. That’s my best guess.

7 Responses

  1. Weekly off-topic reminder:

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  2. I thought you were a Pennsylvania girl/Navy brat. How come you’re giving the Hook ‘Em Horns sign? 😉

  3. By “greasy” amino acids, I would guess you mean amino acids whose R groups are hydrocarbon residues, such as valine, leucine, isoleucine, etc.?

    • Yep, and phenylalanine. There are a couple of tyrosines and about 4 histidines. They have a little bit of lipophilic or aromatic character with some h-bonding capacity. What’s weird is the number of them.
      The other possibility is that the loss of the glycines and shortening of that one segment makes the protein more specific. But then you gotta wonder if it’s more specific for a certain group of people. Like maybe it infects people with San ancestry because there’s a genetic variation in their target protein. Maybe the chunk of ice fits into that metal muffin tin better and the added flexibility isn’t needed. Also, I don’t know where these mutations map to. They’re listed linearly but functioning proteins are 3D. Those mutations could be clustering around a specific place or in several places or scattered. The numbering suggests at least a couple of sites that may turn out yo be next to each other in space.
      Anyway, I should really fire up my laptop and take a look but my current set of tools are so unsuited for it that I kind of think what’s the point. No one really cares what I think or they wouldn’t have eliminated so many of the small molecule drug design positions, which is ironic because it’s our expertise that is kind of needed right now. You need therapeutics as well as vaccines.

      • To the last part: Yeah, that’s the sort of thing which can happen to a society which takes Mammon as its god.

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