#foldit

A protein is a sticky string. There’s two kinds of sticky: orange sticking to orange (”nonpolar” sticky), and red sticking to blue (”polar” sticky). Here’s a short protein, technically so short that we should refer to it as a “peptide”:

You can see that it’s organized into groups of 3, called “residues”: little red bit (a hydrogen), an optional orange bit of some kind (the “side chain”), and a blue bit (a carboxyl). At the ends, the red and blue bits get bigger. The fact that the red and blue bits are always there means that they can be arranged into some simple patterns, assuming there’s room. But let’s talk about the side chains for a moment.

Some side chains end in red and blue bits. These are the “polar” and “charged” side chains, and when the protein tangles itself into the right shape, they’re found on the outside. This is because outside the protein is water, and water molecules have a red part and a blue part, so the side chains want to stick to it. I put a water molecule, to scale, next to the first charged side chain, so you can have a visual. Polar and charged side chains are called “hydrophilic” side chains for this reason.

The pure orange “nonpolar” side chains, meanwhile, gather on the inside, sticking to each other in a gooey mess. They’re the opposite of hydrophilic: hydrophobic. When you achieve that gooey mess, you have “buried your hydrophobics”.

90% of figuring out what shape a protein will tangle up (euphemistically “fold”) into is burying your hydrophobics.

There’s only 20 kinds of side chains in total, and that’s also counting the weird residues with not-quite side chains like proline, that weird bend in the last but one residue in our little peptide, and glycine, the residue with no side chain at all. (Besides a measly hydrogen, and everyone knows hydrogens aren’t real. That’s a computational protein engineering injoke; feel free to use it. The joke is nobody knows exactly where hydrogens are, and nobody cares.) Here’s a family portrait:

I’m not gonna explain any of the weird ones here, because honestly, it’s not super important. Red sticks to blue, orange sticks to orange, and stuff that looks like it’s connected is connected. That’s it, that’s proteins. I guess it’s worth mentioning that the yellow parts are sulfur, but sulfurs are just large, bratty oxygens (the blue bits). They’re not special.

Remember how I said the regular alternation of red bits and blue bits on residues creates some simple, reliable patterns? “Some” is two. Well, technically a few more than two, but nobody really pays attention to the other ones, because they’re just knockoffs of the first two. Here is the first pattern. It’s the favorite pattern of isolated bits of protein with nothing better to do:

This is called an alpha helix. They’re stiff, like rods. You’ll see a lot of these. The other one happens when you lay bits of proteins side by side:

This is called a beta sheet. If you leave a bucket of any protein whatsoever in one place long enough, eventually it’ll fall apart and turn into these. That’s part of why cells have to clean their proteins up: otherwise, it’ll turn into this junk. (”This junk”, on the cellular level, is called amyloid fiber, and is deadly to the cell. On the human scale, it’s called silk, and it’s nice and soft.) But this is also a very structurally useful pattern; it creates tight but flexible weaves. They get shaped into barrels or parts of barrels, usually, but sometimes they get used as walls instead. And sometimes they’re very small and consist of just two short bits that need to get glued together at the sides.

The rest of the protein is just spaghetti, euphemistically called “loops”. The functional bits that attach to stuff outside the protein tend to be on the loops, because the loops are the most flexible and can be posed the most precisely. In real life, proteins are constantly undergoing vibrating motions on every level. The biggest motions are also the slowest; pac-man-shaped proteins will “breathe”, opening and closing at regular intervals. Usually the only time they’ll be able to bind stuff is when they’re open. The takeaway here is that all the stuff inside the protein is gonna wiggle anyway, and you have to make sure it looks the best when it’s wiggled open, if you’re trying to stick something.

Congratulations. That’s everything I know about how proteins get their shapes, pretty much. Your mission is now to make a protein that sticks really well to some important part of the coronavirus’s spikes. The spikes are made of protein, and when they get near an alveolar cell, they open up and jam a lockpick into a “lock” protein called ACE2 on the surface of the cell, which makes the cell sluuurrrp up the virus. Some good ideas are to cover the lockpick so it can’t activate the lock, or to jam the opening and closing mechanism so the spike’s shape gets distorted.

There’s also a couple of other proteins the coronavirus makes that you could try to mess up. A popular target is its two proteases. Viral proteins come like the plastic bits for assemblable toy models: all the pieces are there, but they’re connected together, and you have to break them apart before you can put them together. That’s what the proteases do. (The second protease also cuts off the “to be destroyed” tags that the cell’s proteins keep putting on the viral proteins.) It’s much harder to get your protein drug inside the cells, but once they’re there, they can be as effective as a drug that targets the virus before it gets into the cell. Leave the drug delivery to us. (Or to big pharma, idk. I got a C+ in drug delivery in undergrad, and got it bumped up to a B when I reminded the professor that my attendance grade was low because I was in the psych ward for a chunk of the semester. That’s still more drug delivery than most protein engineers have taken.)

You’re ready!

Here’s a “Getting started with Foldit” tutorial.

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* I first heard of the Rosetta project in a scientific review when I was... 14 ?, but sadly my computer was extremely slow and I couldn’t contribute. I had completely forgotten the name and thought I missed the occasion by a decade. 

I guess it’s never too late.

** A bit like the weeping angels in Doctor Who, who sends you into another time to harvest the potential energy of your unlived lifetime, except minus the part where you are forced to, and the part where you do not get to see the people you love ever again for the rest of your life.