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April 22, 2007
Melting Keys and Squishy Locks
Pretty much the only thing that an interested lay person has heard about ligand binding is the "lock and key" metaphor. I'm not saying that you could walk down the sidewalk getting nods of recognition with it, but if someone's heard anything about how enzymes or receptors work (well, anything correct), that's probably what they've heard.
And there's a lot to it. Many proteins are really, really good at picking out their ligands from crowds of similar compounds. (If they were perfect at it, on the other hand, we drug company types would be out of business). But the lock-and-key metaphor makes the listener believe that both the ligand and the protein are rigid objects, which they most definitely are not. There's no everyday analog to the way that two conformationally mobile objects fit to each other - well, OK, maybe there is, but it's not one that you can safely use for illustrative purposes. Ahem.
The other big breakdown of the lock and key is that it doesn't deal well with the numerous proteins that can recognize more than one ligand for their binding sites. Particularly impressive are the nuclear receptors and the CYP metabolizing enzymes. Both those classes bind a bewildering number of not-very-similar compounds, and they can do it impressively well. They manage the trick by having binding pockets that can drastically change their shapes and charge distributions, as parts of the proteins themselves slide, twist, and flip around. I can't come up with even a vulgar metaphor for that process.
I'm thinking of doing several posts on the limits of metaphor and simplification in science, and if I do, this will be the first. It's a constant struggle not to mistake the picture for the real thing, particularly if the simplification is a pretty useful one. But eventually, no matter how good, the metaphor will thin out on you, and you'll be in the position of a Greek bird pecking at some painted fruit and wondering why it's still hungry.
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