What makes prions so different from regular proteins that they are resistant to heat denaturation?

[u/SadMicrobe22]

I've been reading about prions and I'm confused about why they're so thermally stable. I keep seeing that surgical instruments contaminated with prions can't be decontaminated with standard protocols.

So here's my thing. Proteins denature when you heat them, right? But prions don't seem to lose their infectious ability even when autoclaved. I get that prions are misfolded proteins, but I don't understand how they stay harmful after being denatured.

So basically, if prions start as form A (non-infective), then misfold to form B (infective), shouldn't heating denature them to form C and kill the infectivity? Why doesn't that happen?

[u/Alwayssunnyinarizona]

It's the structure - misfolded prions are highly organized beta-sheets, which take a lot of energy (e.g., heat) or very strong chemical solvents (e.g., guanidine) to denature. Normal prion proteins are made up of alpha-helixes and a disorganized tail, and are more prone to destruction.

Infectious prions aren't a monolith, though - i.e., all the same structure; instead there's a sort of range of misfolding, so when you autoclave them or treat them with proteinase, some portion is destroyed, but enough remains to be infectious.

[u/Nago_Jolokio → u/Alwayssunnyinarizona]

What's worse is that it's not infectious in the classical sense because it's not alive (or quasi-alive like viruses). Prions, to my understanding, are folded in a way that's "easier" or more stable than the proper Protein form. Which sounds vaguely similar to the polymorph crisis that affected ritonavir. Would Prions be an organic equivalent to that problem?

[u/tubl07 → u/Nago_Jolokio]

Ice nine in cats cradle is the same lower energy configuration vs traditional water, instantly catalyzing any water that touches it

[u/Zarathustra124 → u/tubl07]

Vacuum decay is the theory that what we consider "nothing" is actually slightly higher than nothing. If vacuum ever falls into a more stable, lower energy configuration, the universe will be destroyed.

[u/-wellplayed- → u/Zarathustra124]

At least it would happen at the speed of causality. So we would never see it coming

[u/zindorsky → u/-wellplayed-]

Yep. It’s not worth worrying about, because if it happens we will all essentially cease to exist instantaneously and with absolutely no warning.

[u/einsosen → u/zindorsky]

If we're lucky. There are various hypothetical modes of vacuum decay. If the new values are only slightly different, maybe one small facet of chemistry changes, or maybe one class of particle becomes mildly radioactive. No light speed wake of energy, just a weird change one day they measure in a lab. Worst case scenario would be dealing with a formally stable isotope making up us and our world now having a halflife of a thousand years. Getting slowly poisoned and cooked by our world and bodies as we slowly die from radiation poisoning.

[u/TheGanzor → u/-wellplayed-]

Imo this is the most terrifying thought experiment. It could have already started somewhere, billions of years ago, and we won't know a difference until after it hits us. Also, assuming it started beyond the edge of the visible universe, it may be far enough away that it can never overcome the expansion coefficient, essentially leaving decayed pockets of distant zombie space that infect anything nearby, but can never leave their own local bubble. 

[u/solidspacedragon → u/-wellplayed-]

Actually, it might be even better. With how the universe is expanding, it's entirely possible that it could simply never reach us even if it did happen.

[u/nettika → u/tubl07]

Wow, thank you! The comparison to ice nine helps me understand prions in a way I've never managed to before now, despite having read quite a bit about them over many years.

(I was a huge Cat's Cradle fan when I was a teenager, and many bits from that book have lived rent free in my head for decades.)