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May 19, 2008
Empty As Can Be
OK, drugs generally bind to some sort of cavity in a protein. So what’s in that cavity when the drug isn’t there? Well, sometimes it’s the substance that the drug is trying to mimic or block, the body’s own ligand doing what it’s supposed to be doing. But what about when that isn’t occupying the space – what is?
A moment’s thought, and most chemists and biologists will say “water”. That’s mostly true, although it can give a false impression. When you get X-ray crystal structures of enzymes, there’s always water hanging around the protein. But at this scale, any thoughts of bulk water as we know it are extremely misleading. Those are individual water molecules down there, a very different thing.
There seem to be several different sorts of them, for one thing. Some of those waters are essential to the structure of the protein itself – they form hydrogen bonds between key residues of its backbone, and you mess with them at your peril. Others are adventitious, showing up in your X-ray structure in the same way that pedestrians show up in a snapshot of a building’s lobby. (That’s a good metaphor, if I do say so myself, but to work that first set of water molecules into it, you’d have to imagine people stuck against the walls with their arms spread, helping to hold up the building).
And in between those two categories are waters that can interact with both the protein and your drug candidate. They can form bridges between them, or they can be kicked out so that your drug interacts directly. Which is better? Unfortunately, it’s hard to generalize. There are potent compounds that sit in a web of water molecules, and there are others that cozy right up to the protein at every turn.
But there's one oddity that just came out in the literature. This one's weird enough to deserve its own paper: the protein beta-lactoglobulin appears to have a large binding site that's completely empty of water molecules. It's a site for large lipids to bind, so it makes sense that it would be a greasy environment that wouldn't be friendly to a lot of water, but completely empty? That's a first, as far as I know. When you think about it, that's quite weird: inside that protein is a small zone that's a harder vacuum than anything even seen in the lab: there's nothing there at all. It's a small bit of interstellar space, sitting inside a protein from cow blood. Nature abhors a vacuum, but apparently not this one.
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