eli5 How does just folding a protein a different way make it do a completely different thing?

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eli5 How does just folding a protein a different way make it do a completely different thing?

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Proteins work by chemically interacting with stuff around them. That depends, almost entirely, on what atoms/electrons/bonds the protein exposes on the *outside*, and their location relative to each other. That depends, almost entirely, on how the protein folded. Stuff on the inside is much harder to interact with and where stuff is on the outside has a huge influence on what it will readily react with.

When people describe proteins being “key” to a biological “lock”, it’s the configuration of the outside of the protein that forms the geometry of the key.

Imagine that a protein is a machine like a car. Each part of the car has a specific function or role for meeting a particular goal. Seat belts are designed in a very specific way and can latch into a buckle. A steering wheel must be connected to the wheels in the right way. Under the hood of the car, the engine and all components must be hooked up exactly to carry out their function.

If you were to randomly rearrange any of these pieces in the car, it might do something different or fail to function at all. The car exists in a very specific way for the function it was designed to do. There is a chance that rearranging parts in some way might lead to something functional but most likely the car would be broken in some way.

In the same way, a protein evolved to fold into its specific shape for a purpose. Folding the protein a different way is much like rearranging the parts (domains) of the protein. It’s unlikely to produce a functioning protein but perhaps if you were lucky you could stumble upon another configuration that had a specific, new function.

Because the folding gives you the shape, which gives you the function.

If you crumple a piece of paper into a little ball, you can roll it across the table. If you fold an identical piece of paper into a paper airplane, it can fly – but can’t roll at all. If you roll another identical piece of paper into a tube, it can roll really well in one direction but not at all in the other direction…

See what I mean? They’re all the same paper, but how you fold/manipulate it determines what the resulting object can do.

The art of Origami is folding a piece of paper into different shapes.

There are hundreds of different shapes a dollar bill can be folded into.

Each shape not only looks different, but end up different sizes, as well as can do different things, yet ALL started with the same dollar bill.

People have posted lock and key analogies, puzzle piece analogies, etc…. but it is a lot, lot more subtle than that.

Imagine a 3D game of tetris. The next dropping piece not only has to fit the available pattern of just one protein, but of all of the other proteins that have also previously interlocked….

And then, to make it even more wild and difficult, the 3D tetris pieces are magnetic, with different Norths and Souths. The next piece not only has to fit perfectly in the available hole, but the magnets have to match too. North to South, South to north. Throw in one wrong N-N area, and pooey! Even if there was a physical match, the pairing is rejected due to wrong magnetics.

Imagine you have a set of screwdrivers. The head of each screwdriver is made of the same stuff, but since they are shaped differently they will fit into different screws.

Now, proteins are a bit more complex. The differences in folding not only created the different head shapes of the metaphorical screwdriver, but it also exposes a different set of chemicals as well. When the protein fits into a chemical “screw”, the chemicals exposed by the folds get used up in the reactions. These means that depending on the folding, a single protein can do radically different things.