Could someone ELI5 why proteins fold in a unique way? Why can't there be multiple "valid" ways for them to fold (ignoring mirror symmetries)?
The explanation why proteins typically only adopt one fold is not in the process of folding itself. But misfolding is really problematic for the cell, and there are various mechanisms to manage it. A misfolded protein is at best useless, and as you can see with prions can also be actively harmful. The cell has chaperones that help proteins fold, and it has quality control mechanisms that try to remove misfolded proteins before they are released into the cell.
But one major factor is evolution, proteins that fold reliably are selected over proteins that can fold into unproductive or harmful conformations. So the proteins we tend to look at already have been selected for their folding properties to some extent.
As others have stated, misfoldings do occur, and the protein is trying to achieve its lowest energy conformation, but the simplest answer is that we don't have a complete answer, hence the desire to come up with a reliable computational solution. We know how certain residues affect tertiary structure, and we know the measurements of secondary structures with a surprising degree of accuracy, but for a protein with potentially hundreds of residues, there are simply too many degrees of freedom to simply tack on amino acids and come up with a structure (although this is essentially the approach that markov chain, monte carlo solutions use).
[This article gives a pretty good synopsis of where computational approaches to the protein folding problem stand.](https://moalquraishi.wordpress.com/2018/12/09/alphafold-casp...)
What I was getting at here is that the answer to the question "does every protein have a default native conformation" is "yes."
I'm not sure if every possible sequence of amino acids has a unique dominant folding. But ones that don't, wouldn't be nearly as useful biologically, because you couldn't rely on them to do their jobs. So they would not be selected for. The ones that actually get coded for by genes fold up more consistently.
Wouldn't a 20% chance of a novel, useful interaction and 80% chance of no effect be almost as good if you are producing a lot of them?
In the situation you describe, the answer is often "yes" and that's how you end up with evolution. Let's say you have a gene that makes a protein that digests glucose. And then one day, your cell messed up when replicating and accidentally made an extra copy of that gene. Well now you have an extra copy of that gene that isn't under purifying selection. It's redundant. It can mutate but as long as you have the first copy, you're ok. And eventually it mutates away from being good at digesting glucose. It can do it a little bit, but it's not great. Maybe it's 20% as effective as it originally was. But you have another gene that's still 100% effective so you don't even notice.
Now we have a protein that really doesn't do anything bad... It just doesn't do much good either. And since it isn't subject to purifying selection, every round of replication it keeps mutating. Until all of a sudden, it mutates into something that can digest lactose. Now, you have an evolutionary advantage from a protein that first had to get bad at binding glucose, before it could benefit you. But evolution has no foresight, so it didn't know. So it took getting rid of purifying selection to make it happen. But now as you come to rely on lactose, that protein will wind up back under purifying selection and become "fixed".
So now let's consider an alternative situation. You only have one gene that can digest glucose. If it mutates to be 20% effective, you will at best grow only 20% as fast as your competitors. Maybe you even die and become an evolutionary dead end. In that case, it is an extreme disadvantage to have a protein that can't do its job reliably, and organisms that don't have a malfunctioning variant will grow better and pass on their genetic material to more offspring, until you are eventually outcompeted and go extinct.
We can also imagine another scenario. Your glucose digesting protein mutates into something that can still bind glucose, but cant digest it. Then the glucose remains stuck to the protein, producing no energy, and becomes a waste for the cell. That is actively harmful and will likely kill the cell very quickly.
So to answer your question: it depends
My recollection is that snails can reproduce either sexually or asexually and they preferentially reproduce sexually in stressful environments and asexually in environments that make staying the same more advantageous.
Sickle Cell is protective against malaria. Sickle Cell trait is protective without causing Sickle Cell Anemia, which is a horrible condition. So one copy of the mutation and you are more likely to survive in an area where malaria is prevalent and two copies and you are jacked up, but maybe less jacked up than with malaria.
Some studies suggest that Cystic Fibrosis is a predominantly Caucasian disorder because having one copy of the gene is protective against certain disease that were sweeping through Europe at one time. Two copies tends to kill people gruesomely at young ages.
So I think generally speaking the answer is that species seem to seek mutations when what they are doing currently isn't working and seek stability when what they are doing currently is working.
Also I have read that it is believed that half or more of all human pregnancies probably end in the first two weeks and result in a heavier-than-normal period without the woman even realizing she was ever pregnant in most cases because those fetuses are simply not viable. Laying bets on "Will this novel mutation or novel combination work?" tends to get a result of "Nope. It so doesn't work, it's not worth investing precious resources in to bring the baby to term and let it be born."
We mutate more when it is "mutate or die" and less when mutating is the thing more likely to kill you.
Proteins naturally fold into a shape where they have the lowest "potential energy". There are several useful metaphors to explain what "lowest potential energy" means and why the proteins are attracted to the shape with the lowest potential energy.
In "the real world", an object's "altitude" is a form of potential energy. A ball on a hill will roll down hill until it settles into the lowest valley it can — the place where its potential energy is lowest. Balls roll downhill to the place of lowest potential energy, and proteins fold into the shape in which they contain the lowest potential energy.
You can also think of a fresh protein as a stretched out spring. The stresses in the spring from being stretched out of shape are a form of potential energy. The spring will contract until it is completely relaxed so there is the minimum amount of "springy" potential energy remaining. Springs contract into the shape that is most "relaxed" and has the lowest potential energy, and proteins fold into a shape having the lowest potential energy.
If the protein was to fold into any other shape, there would still be some potential energy left in the protein that could be relieved if only the protein could get itself folded into the "correct" shape. If the rolling ball gets stuck on a rock or the spring gets snagged and can't completely relax, both objects would be stuck with a higher potential energy than they would if the ball reached the bottom of the hill or if the spring were allowed to fully relax.
Hopefully this explains why there is a single shape that proteins are most attracted to when folding. But, it doesn't explain why other shapes are somehow "invalid".
Proteins are like pieces of cellular or chemical "machinery". Like the parts of a mechanical machine, the protein's shape is part of what defines how the protein works, what it can "do", and how it fits together with other pieces of the cellular machine. And, since "correctly" folded proteins always have the same shape, "machines" can be built with them.
When proteins are misfolded, they have a different shape from the shape that all of the other machinery expects. Like a gear without teeth cut into it, the misfolded protein doesn't perform the function that it, as part of a cellular machine, is supposed to perform. The protein might "jam" the machine up or even cause the machine to malfunction and start doing something completely unintended.
I hope this comment is correct enough and clear enough for an ELI5 — though it might be more of an ELI15.
A protein can have many different, stable conformations. Those conformations depend on the chemical environment, and any interactions the protein is making. Basically they alter the lowest energy to be a different arrangement.
However, basic elements of the fold, with a few exceptions, will never change. We call these secondary structure elements, and they are limited by phi and psi angles on the dihedral C-N peptide bond. These secondary structure elements are thought to form before the protein is even fully synthesized, and are extremely difficult to undo. However, the spatial relationship between these elements is much more dynamic depending on what the protein is doing.
The ELI5 version is basically that proteins will have a basic shape, and they can wiggle around that shape, but can't really radically change because it would take too much energy
So if you have, for example, cystic fibrosis, you have a defect in a cell channel called the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and its job is to handle traffic of specific molecules into and out of the cell.
So your question is a little like asking "Why can't the cell just spit out random tools that randomly do different things?" And the answer is that it's not helpful to the cell if wrenches sometimes randomly morph into hammers or screw drivers when you ordered X number of wrenches because DNA is the blueprint instructions for creating this tiny little factory of life called a cell.
It's coded to create wrenches and it's coded to create a specific number of wrenches and it's not necessarily more useful for misfolds to turn into random other tools instead of the pile of junk that misfolds create.