Is it possible or likely that the folding process is more procedurally deterministic than it seems? (given sequence, temperature etc) The degrees of freedom perhaps seem intractable because we don't know what steps the structure takes between the linear extrusion and final fold. AlphaFold, if I understand correctly, doesn't attempt to solve this problem. Your comment implies we should be skeptical of it because it's solving a potentially-intractable problem; perhaps it's both tractable, and AlphaFold doesn't solve it.
Let's say you have a car (or lego set etc). The number of possible ways the parts could go together are astronomical! Does that mean it's not possible to figure out how it fits together, or how you might build one?
Yes, if you have a Lego set, or a series of car parts, there are many ways to put them together to make something. What AF is doing as far as I understand is essentially looking at a catalog of all Lego sets ever produced, or all car models ever produced, and choosing one that most closely matches the pieces it is seeing.
But there is no reason to expect this process to produce the right end-result for a Lego set that has never been seen before.
Yes, but that competition is using lots of proteins that are similar to other known proteins, as far as I understand.
There is also a lot of sub-structure that helps - similar parts of proteins tend to fold in similar ways, so even if you don't have real predictive power on unknown sequences, you may do quite well for a protein that is 90% the same as one in the training set - you will be quite correct on ~90% of the folds, even if your pretty way off on the remaining 10%.
Note that all of this is not to minimize the success of what AlphaFold achieved. I am just trying to explain how you can do well at this problem without having discovered some deeper deterministic structure in protein folds.
Yes, but many proteins can be boiled down to basically two classes - the folded portion, and the unfolded portion. The folded portions are typically shared (shared is a loose term, there's a lot of leeway) among almost all proteins.
So, I can pull a protein out of thin air and there's a good chance it'll have an overall fold similar to another protein that's got a structure. Unfortunately, the devil is almost always in the details. An amino acid here or there, a short extension here or there, a missing charged residue or an extra glycine and now you have a different target and entirely different behavior in a biological system.
One cool thing I found actually, was a protein in an Archaeal virus had no known homology a few years ago, but when I checked the other day, it now matches most closely to an (otherwise thought to be) entirely synthetic protein out of David Baker's lab at UW. Which means this Archeal virus and David Baker converged on the same fold somehow (likely because it was "stable").
Let's say you have a car (or lego set etc). The number of possible ways the parts could go together are astronomical! Does that mean it's not possible to figure out how it fits together, or how you might build one?