[elcritch]

We already have a precise and accurate theory for protein folding. What we don’t have is the computational power to do true precise simulations at a scale and speed we’d like.

In many aspects a huge tangled barely documented code base written by inexperienced grad students of quantum shortcuts, err, perturbative methods isn’t that much more or less intelligible than an AI model learning those same methods.

[dekhn]

What "precise and accurate theory for protein folding" exists?

Nobody has been able to demonstrate convincingly that any simulation or theory method can reliably predict the folding trajectory of anything but the simplest peptides.

[elcritch]

> What "precise and accurate theory for protein folding" exists?

It’s called Quantum Mechanics.

> Nobody has been able to demonstrate convincingly that any simulation or theory method can reliably predict the folding trajectory of anything but the simplest peptides.

No we don’t have simplified models or specialized theories to reduce the computational complexity enough to efficiently solve the QM or even molecular dynamics systems needed to predict protein folding for more than the simplest peptides.

Granted, it’s common to mix up things and say that not having a computationally tractable models means we don’t have precise and accurate theory of PF. Something like [0] resulting in an accurate, precise, and fast theory of protein folding would be incredibly valuable. This however, may not be possible outside specific cases. Though I believe AlphaFold indicates otherwise as it appears life has evolved various building blocks which enable a simpler physics of PF tractable to evolutionary processes.

Quantum computing however could change that [1]. If practical QM is feasible that is, which it’s beginning to look more and more likely. Some say QC is already proven and just needs scaled up.

0: https://en.m.wikipedia.org/wiki/Folding_funnel 1: https://www.nature.com/articles/s41534-021-00368-4

[dekhn]

I don't think anybody is 100% certain that doing a full quantum simulation of a protein (in a box of water) would recapitulate the dynamics of protein folding. It seems like a totally reasonable claim, but one that could not really be evaluated.

If you have a paper that makes a strong argument around this claim, I'd love to see it. BTW- regarding folding funnels, I learned protein folding from Ken Dill as a grad student in biophysics at UCSF, and used to run MD simulations of nucleic acids and proteins. I don't think anybody in the field wants to waste the time worrying about running full quantum simulations of protein folding, it would be prohibitevly expensive even with far better QM simulators than we have now (IE, n squared or better).

Also the article you linked- they are trying to find the optimal structure (called fold by some in the field). That's not protein folding- it's ground state de novo structure prediction. Protein folding is the process by which an unfolded protein adopts the structured state, and most proteins don't actually adopt some single static structure but tend to interconvert between several different substructes that are all kinetically accessible.

[elcritch]

> I don't think anybody is 100% certain that doing a full quantum simulation of a protein (in a box of water) would recapitulate the dynamics of protein folding.

True, until it's experimentally shown there's still some possibility QM wouldn't suffice. Though I've not read anything that'd give reason to believe QM couldn't capture the dynamic behavior of folding, unlike the uncertainty around dark matter or quantum supremacy or quantum gravity.

Though it might be practically impossible to setup a simulation using QM which could faithfully capture true protein folding. That seems more likely.

> It seems like a totally reasonable claim, but one that could not really be evaluated.

If quantum supremeacy holds, my hunch would be that it would be feasible to evaluate it one day.

The paper I linked was mostly to showcase that there seem to be approaches utilizing quantum computing to speed up solving QM simulations. We're still in the early days of quantum computing algorithms and it's unclear what's possible yet. Tackling a dynamic system like a unfolded protein folding is certainly a ways away though!

> Also the article you linked- they are trying to find the optimal structure (called fold by some in the field). That's not protein folding- it's ground state de novo structure prediction.

Thanks! I haven't worked on quantum chemistry for many years, and only tangentially on protein folding, so useful to know the terminology. The meta table states and that whole possibility of folding states / pathways / etc fascinates me as potentially being emergent property of protein folding physics and biology as we know it.

[parodysbird]

> It’s called Quantum Mechanics.

Nobody is suggesting anything entails a possible violation of quantum mechanics, so yes, obviously any system under inquiry is assumed to abide by QM.