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mikedensem t1_jbu7w6x wrote

Reply to comment by Thornwalker_ in What exactly is going on when a protein (or other molecule) binds with a receptor? by Eat-A-Torus

So, do most non-ligand molecules get kicked away due to a mismatch in bonding charges? How does the receptor repel other stuff?

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NeverPlayF6 t1_jbuxqby wrote

If the ligand doesn't fit, it doesn't have to be "kicked away." More like "randomly bounced away." The receptor doesn't have to do anything for the non-ligand molecule to move away. If you look at the wiki for Brownian motion you'll see how molecules are in constant motion. Things suspended in a fluid are not just sitting still... They're bouncing around like a room full of caffeinated 5 year olds.

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jfincher42 t1_jbv4ifp wrote

So in that case, how critical is the positioning of the ligand and the receptor?

Going back to the lock and key analogy, sure, my key opens the lock, but only if it's inserted into the keyhole at a specific angle and orientation. I can't insert it backwards, or sideways, or even twisted a few degrees off axis and expect it to work.

If my key is subject to Brownian motion, even if there were m/b/tr-illions of them bouncing around outside the lock, I wouldn't expect one to fit within a given time frame.

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[deleted] t1_jbvbr66 wrote

It depends, but many chemical reactions are sensitive to orientation. Enzymes kind of guide the ligand in with a potential energy gradient, so it's not just a lock and key analogy, but more like a lock and a key, and a funnel for your drunk self to get the key into the keyhole at 2am

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Harsimaja t1_jbvud4b wrote

One simplistic way to think about it would be that while random chance has a lot to do with whether a molecule gets to the vicinty of a receptor, once it’s vaguely in the neighbourhood it isn’t all just random luck getting into perfect binding position: chemistry is ultimately electromagnetic, and opposite charges attract by a real force, so the more positive parts that want to bind to negative parts etc., so the right parts of the receptor and molecule will be attracted accordingly until they bind.

Everything in physics is trying to find a local optimum, and there are real forces guiding them to that optimum.

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slashdave t1_jbvx27g wrote

You need to think in terms of statistical mechanics. These systems happen in an ensemble. The system has many allowed states, some bound, some not bound. The occupancy of these states depend on the free energy difference of the two states. So we are really talking about probability. In many cases, it is the solubility of the ligand that matters most (how much the ligand prefers to be surrounded by water).

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monkeyselbo t1_jbv1ijo wrote

Some ligands will have ionic areas on the molecule (which is what I suppose you mean by charges), such as an amino group (R-NH3+ at physiologic pH) or a carboxyl group (R-COO-). And amino acid side chains within the protein binding site can be like that as well. But the presence of a charged functional group is not necessary for ligand binding. You can have ion-dipole interactions (there would be a charged functional group with that), dipole-dipole (no charged group), hydrogen bonds (no charged group), and hydrophobic van der Waals interactions (no charged group) that all increase binding affinity. There probably are issues regarding the presence of water molecules as well (aqueous solubility), but that's a supposition on my part.

We really don't use the term bonding for the insertion of a ligand into a protein binding site. It's binding, a much more general term. You don't actually form a bond (covalent, ionic), but of course you can have a hydrogen bond, which are transient and reversible. The most important thing for a good fit, however, is a matching of the shape/conformation of the molecules. The hand in a glove analogy is a good one.

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