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In Silico

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.

30 comments on “Melting Keys and Squishy Locks”

  1. Milo says:

    This is a great topic. I have always been amused at the fact that even established researchers can get hooked on the metaphoric way of thinking, so much so that they inadvertently put on a set of blinders.

  2. Martin Löwdin says:

    As a student of rhetoric (of the philosophy-heavy Euro variety) I really like this initiative. Metaphors are strong tools and always in dire need of scrutiny, not just because they often act as blinders but because they, in essence, define our whole reality.

  3. Mark H says:

    Have you seen Joel Spolosky’s Law of Leaky Abstrations? It’s sort of the same idea, but he applies it to software.
    Most of the reason I read this blog is so that my abstractions get more sophisticated. (and, how high-reliability things get formed out of seeming chaos.)

  4. milkshake says:

    Ahh, now I understand why the pictures of ligand-in-da-protein co-crystals are so exciting to behold. They are X-ray-rated.

  5. Eric says:

    I personally like the “hand and glove” metaphor for ligand-enzyme binding. It includes chirality, “induced fit”, promiscuity of ligands, and so on, and illustrates some of the difficulty of designing a “hand” that only fits in one “glove.”

  6. Andre H says:

    My favorite extension of the “hand in glove” metaphor is “rubber hand in rubber glove”.

  7. pieman says:

    Milo, I agree that science metaphors that put the blinkers on researchers is a great topic. Perhaps more controversialy, I wonder if there are any industry-based R&D metaphors that are misinterpreted by the academic community. For example, does the image of linearity conjured up by the drug pipeline lead to non-industry researchers lacking a full appreciation of the circularity of drug discovery and development?

  8. Monte Davis says:

    Yessssssss! Looking forward to it.
    You know my hobbyhorse from previous posts: as well as being both floppy and specific beyond intuition, the co-conformation is very very fast and very very frequent compared to even our best visualizations.

  9. I can’t possibly imagine what commonplace occurrence you are thinking of, but an obvious one is shaking hands. Pick a partner and try to do it keeping each hand rigid. Alternatively, try to do it when one person starts with a fist. Initial shape matters, but so does induced fit!

  10. Morten says:

    What about entropy loss upon ligand binding? How do you analogue that? … Ok, I came up with one on my own (took me about three seconds) but alas not really kiddie friendly. Floppiness is always bad apparently.

  11. Wavefunction says:

    “Good scientists can see analgies between theories. The best scientists can see analogies between analogies”-
    Stan Ulam, Hungarian mathematician

  12. Wavefunction says:

    Sorry, make that Polish mathematician.Too many famous Hungarian mathematicians and physicists in that time!

  13. Mataphoricly lost says:

    My favorite metaphor came from my previous director who one described an ailing project as a “a blind man in a dark room trying to find a nonexistant black cat.”

  14. RKN says:

    I think one of the most misleading metaphors recently was Dawkins’ “The Selfish Gene.”

  15. curiousGeorge says:

    For most self-referential, I nominate the meme meme:

  16. Wavefunction says:

    RKN: True, although it was other people who misunderstood what Dawkins was saying.

  17. “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.”

    It’s an octopus making love to a plate of spaghetti.

  18. Wavefunction says:

    Vulgar Metaphor: Bravo!

  19. srp says:

    The enzyme thing sounds like a good prospect for an animated, pictorial metaphor. Colored balls connected by sticks thrashing and flexing and merging and releasing…OK, going to stop now.

  20. milkshake says:

    Speaking of vulgar methaphors: Derek, have you ever posted a goatse picture on your website? Check out mine. I have to advertise this here because 600 views later nobody noticed something’s wrong!

  21. ac says:

    I once took a class from Ron Breslow in which he repeatedly bashed the lock and key model in favor of the Venus flytrap model. His argument is that the flytrap analogy is better because ligands constantly go past the receptor but the enzyme only folds down on (“eats”) a certain type of “prey”.
    If for no other reason, I like using this analogy with non-scientists because it draws on their knowledge of science to explain the idea. Even if there’s absolutely no connection between tropical botany and medicinal chemistry, the comparison seems to evoke images of guys in lab coats in their minds.

  22. CJ Croy says:

    Milkshake: I think there’s a good chance he has never experienced the joy of goatse. I think he’s better for it.

    My favorite metaphor is one I heard for prion disorders: “Angry shapes”.

  23. CJ Croy says:

    Milkshake: I think there’s a good chance he has never experienced the joy of goatse. I think he’s better for it.

    My favorite metaphor is one I heard for prion disorders: “Angry shapes”.

  24. MolecularGeek says:

    It’s probably too rigid-body and ordered to satisfy the best parts of the metaphor, but how about those solid puzzles that are stacked together and that depend on the right bits sliding together to stay in the desired shape?

  25. wjs says:

    Reading all this reminds me of one of my favorite metaphores. It was presented by Sei Otsuka while visiting Cornell in 1980. He said “It is more difficult for a right-handed man to open the kimono of a gisha than for a left-handed man because the kimono is fastened on the left side. Thus, the gisha is an enentioselective catalyst.”

  26. Hap says:

    Wouldn’t the geisha technically be an enantioselective reagent (she isn’t exactly the same before (reaction) as after)? In addition, I wouldn’t figure that opening the kimono would be the rate-determining step, so that even though the rate of opening the kimono depends on the handedness of her vistor, the overall rate of reaction doesn’t.

  27. rosko says:

    The Venus flytrap analogy is not only a good metaphor, it actually is a good picture of what is really going on (in a detailed sense) in certain cases. There even is a common fold in certain receptors (for instance metabotropic glutamate and other Class C GPCRs, for those of you who know what those are) called the “Venus flytrap domain”, and it consists of two lobes that snap shut when an agonist binds to residues on both lobes (or is pried apart when the ligand is too big–and therefore an antagonist).
    And wjs, that’s one of the funniest scientific metaphors I’ve heard. Another is from one of my professors, who was describing how many antibiotics inhibit protein synthesis by blocking the peptide exit channel on the large ribosomal subunit: He told us to remember the mechanism as “molecular constipation”.

  28. Sometimes I think using these kinds of metaphors at all can be a bad idea, because people get them stuck in their heads and can’t let go, and it colors everything they think afterwards. In basic high-school-level chemistry there a couple of different popular models that are both terribly wrong: the atom as a solar system, and the Bohr model. The former is worse, but the Bohr model is also spectacularly lousy. Electrons just don’t behave like miniature charged marbles, and if you assume they do, you get very confused later in the semester when you try to reconcile your conception of atoms with actual chemistry.
    Other fields have some pretty terrible-but-popular models and metaphors as well. In theology, for instance, the doctrine of the trinity is often explained (very badly) using an egg or a clover, and these analogies cause much more confusion than they alleviate. In physics, the “tied together with a piece of string” model for orbiting celestial objects is pretty horrible.
    In math, a lot of undergrads have a terrible time when they first hit modern algebra, because they can’t get real-number operations out of their heads. I guess that one’s unavoidable, though: we can’t very well stop teaching real number addition and multiplication in grade school, because it’s too practically useful in fields other than math. Still, it’s another example of how an oversimplified-but-concrete view of something gets embedded in the mind and hinders a deeper understanding later.

  29. srp says:

    Did you ever notice that the classic “atom” logo isn’t really like the solar system because the orbits intersect on perpendicular major axes? It’s a great piece of graphics even if it’s lousy science.
    BTW, my high school chemistry book described the electrons as being like a swarm of bees with the hive as the nucleus.

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