Omicron spike protein should be impossible, according to DI's Brian Miller

[Rumraket (Mikkel R.)]

@BenKissling

Well as long as it’s only mostly dead, that’s a very different thing than all dead.

Mostly dead implies a significant reduction in viral fitness given the crucial function of this protein to the lifecycle of the virus. There’s no evidence it has suffered any reduction in fitness. On the contrary. Omicron is rising in frequency, and rapidly outcompeting the delta variant. It would be very odd if it was accomplishing this with a protein that falls apart much more frequently due to destabilizing mutations, than it’s delta-variant competitors.

Now the broader context of Brian Miller’s talk is his attempt to try to debunk the reality that proteins can evolve to change functions, such that one protein performing some function A can be mutated and co-opted to perform a different function B (in the video talk he casts this in the context of the flagellum filament protein flagellin evolving from a protein with a different function than being a filament). He is quite clearly arguing that this can’t happen, since apparently he appears to think the accumulation of mutations in some pre-flagellin protein would render it nonfunctional long before it acquires the ability to function as a flagellin.

So I’m just left wondering here. When is the spike protein going to fully fall apart? Why do we have so much evidence of many other proteins diverging, and having already diverged, from their common ancestors, well beyond the sorts of limitations(be that 3-10 total mutations, or ~10% of total protein sequence) Brian Miller is misreading his references to imply?

I must repeat what I wrote in this thread:

@Rumraket

@Daniel_Arant

My first question is an overarching one: why is it simply assumed that one homologous protein can evolve into its homologue?

I’d flip this question around on it’s head and ask, if we can see that two proteins that share something like only 15% sequence similarity are still capable of performing essentially the same function (bind the same molecule or catalyze the same biochemical reaction), then why should we not think this?

If they can be THAT different yet still remain functional in the same way, then why should we think somewhere in the range of similarities between 100% and 15% there is some gap of nonfunctionality?

Presumably two proteins which are totally identical would not merit any doubt at all. So if we make them 99% identical, that’d still plausibly make them able to remain functional. Even if they have some degree of constraint on how much they can change before they stop being able to function, 99% seems to be similar enough that it shouldn’t be a problem. And the same at 98%.

We can imagine we keep going and at some point, maybe we start to think they’re beginning to be so dissimilar it might impact the function? Say we think maybe at 50% similarity we have some intuition that a lot of the protein sequence has changed, so how can it still retain the same structure or function?
But then we discover a variant of that protein that is 15% similar to the other one and yet it still functions. But then doesn’t that immediately imply the entire range spanning 100 to 15% must contain functional sequences? Shouldn’t that cause us to think there really is a pathway all the way from 100% to 15% similarity? We thought maybe 50% was some lower limit of similarity we couldn’t go beyond without breaking the function or structure, and yet now we find one that only has 15% similarity and it remains able to perform the function.

If we can find two proteins that adopt a similar structure which are 90% similar, and others that are 80% similar that still adopt the same structure and function, and then others that are 15%, how is this not exactly what we would expect to have if these proteins really did evolve from a common ancestor over very long periods of time?

And if these proteins are part of some larger structure, and other proteins in that structure exhibit the same pattern, and they show the same sort of gradual decrease in similarity with the distance of relationships between the species that carry them, then what could really justify the idea that they can’t have diverged gradually over that enormous period of time?