"Thermodynamically, the range of possible conformations, once folded, is only so big," <- this is not even remotely true, especially in the context of actual biology. Many proteins undergo constant small transitions between nearby substates, this is known to be important, and doesn't occur in flash frozen proteins (or is greatly reduced). And there are much, much larger conformational changes that can be unlocked in specific conditions- absolutely not going to happen once frozen. There's no real guarantee your sample population of frozen proteins are going to include the full biologically relevent set of conformations.
(my background was in structural biology and I worked next to folks who helped Wah Chiu some ~20 years ago, but my experience in protein dynamics is fairly broad)
Ultimtately, I think we:re talking about different things. From mu perspective, you're making a very different statement here than what you made above. The earlier comment alluded that the conformational dynamics seen in Cryo-EM structures may not be biologically relevant. That is the claim I contested, and very different than the one you make in this comment (which I mostly agree with) which is that EM only captures a small amount of biologically relevant states.
>"Thermodynamically, the range of possible conformations, once folded, is only so big," <- this is not even remotely true, especially in the context of actual biology.
There's a bit of a shoreline paradox at work here. The range is quite small for the folded structure, vs the total possible sampling space. It seems now that you're talking about things at a much finer resolution (which is fine), which didn't seem relevant to your initial suggestion that there's debate around whether EM models are biologically relevant.
Like I said, ongoing problem, here is a recent paper addressing this : https://www.nature.com/articles/s42256-020-00290-y and another: https://www.nature.com/articles/s41592-020-0925-6
(my background was in structural biology and I worked next to folks who helped Wah Chiu some ~20 years ago, but my experience in protein dynamics is fairly broad)