[Sodel]

Someone will probably need to correct me, but here's how I understand it.

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.

[COGlory]

To expand on that (great explanation btw) and to get at something the original question was asking:

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