Just a quick comment here. The DI’s Brian Miller has been going around saying (on this forum, on EN&S[2,3], and in youtube videos) that by the time a protein has accumulated 3 mutations it should already have lost so much stability it couldn’t possibly evolve much more, and by 10 it should be a misfolding piece of junk.
Meanwhile, the Omicron variant’s spike protein with mutations highlighted:
We are also told by ID-creationist math that to accumulate two mutations would take some absurd amount of time, and by the time you need 10 mutations to have accumulated in a protein the universe will have undergone heat death. Yes it’s that infamous “waiting time problem”. Remember, they think even “waiting for two mutations” is a problem.
This may look like a problem for ID, but it’s pretty easy to tackle. Either ignore it, or, if I may channel my coworker for a moment, he would say since it’s mathematically impossible for so many functional mutations to occur and yet omicron has those mutations… it’s designed!
From your first reference, Miller on the Tawfik study:
“The 21 studied proteins all show the same distribution of stability reduction for mutations, so nearly all globular proteins would have a similar minimum rarity in sequence space near an optimized sequence. And, nearly all would become entirely nonfunctional with nearly any random combination of mutations leading to a 10% sequence change.”
Just a quick check of the Wikipedia for the omicron variant shows about 30 substitutions and a number of other indels and such totaling 60 mutations. The spike protein is 1,273 amino acids long. What was that about math again?
The spike protein also consists of two subunits, each of which consist of multiple domains. Some of which are even known to be able to fold autonomously, without being part of the entire spike protein(in particular the receptor binding domain alone can do this, and it’s just about 200 amino acids long). The RBD alone has about 15 mutations total.
Whichever way you look at it, this protein should be pretty much half-way if not entirely dead if Miller’s confused assertions reflected reality.
Now the real problem with his assertion is his misreadings of the literature he cites. Particularly what he takes the Tawfik study to imply.
It is true that the average effect of mutation without selection has a destabilizing effect on protein structure, and it also makes sense that the magnitude of the destabilizing effect of each individual mutation would diminish as the protein grows larger (because, basically, the larger the protein the more internal surface area can “stick” together so any individual amino acid would be a smaller part of the structure). But Brian Miller takes this to imply one protein can’t evolve to acquire a new function (in the video he basically asserts that the flagellin protein of the flagellum couldn’t evolve from a protein with a different function) by accumulating mutations, because he appears to not understand that purifying selection can maintain structural stability of a protein against destabilizing mutations, such that you can continue to accumulate mutations well beyond the naive threshold you would reach without selection. His idea seems to be that if two proteins are too different from each other in sequence, then there is no way to get from one functional protein to another even if they’re as similar as 90%, because by the time 10% of the sequence has changed the protein should be completely nonfunctional.
That is absurd.
We know of examples of proteins that diverge in sequence basically all the way from 100% to 15%(or even below in some cases) sequence similarity, while retaining a functional and stable structure. And we have divergent superfamilies where we know of variants that diverge at large portions of the way, at increments on the level of 1-2% at a time. 100%-98%-96%-94%(…)10%-8%-5%-3%. Incidentally there was a good example in table 2 of the paper I referenced in this thread(and again here).
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?
One of the side effects of a loss of stability is the specificity in binding is reduced, allowing weak binding to more targets. For obvious reasons, that does not necessarily result in lower fitness. The problem here is that fitness defined according to evolutionary theory is not a helpful model in understanding protein structure or function.
Let’s look at the specific data here, Ben, rather than traffic in generalities.
From the original variant to omicron we observe 30+ mutations. If I am understanding you correctly, you would expect the omicron variant to be less stable and to bind less specifically to the ACE-2 receptor. Is this a fair and accurate reading of your statements?