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-Metacelsus- t1_jbsw0tq wrote

Receptors are proteins, which are made up of amino acids that fold into a particular 3-dimensional shape. Different amino acids can also have different properties such as positive and negative charges, hydrophobic or hydrophilic side chains, etc.

Receptors can also be modified with sugars, lipids, etc. but the ligand binding site is usually just amino acids.

When a ligand (protein or other molecule) binds to the receptor, it will interact with the amino acids in the binding site, based on their 3D shape and physical properties (charge, hydrogen bonding, etc.) The binding affinity of the ligand will depend on how strongly it interacts with the binding site. This is how the receptors establish selectivity for binding some molecules instead of others.

You can think of the binding event like a hand fitting into a glove. The glove will change shape a bit when the hand goes into it. This conformational change in the receptor can cause downstream biological effects, depending on the function of the receptor. Many receptors are kinases which phosphorylate proteins when the ligand is bound.

Also, some inhibitors (called competitive inhibitors) will bind to the receptor and not cause conformational changes like the normal ligand, but still occupy the binding site.

Regarding the question of rigidity/solidity, proteins can be more or less flexible (depending on the protein) but the individual bonds are pretty rigid, and most receptors will have only a few stable conformations.

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operationarclightII t1_jbucuu4 wrote

There have been updated models of receptor and ligand interaction. A big one that pharmacologists would point to is conformational selection, in which the receptor is constantly flipping between active, intermediate, and inactive states, even without a ligand. The presence of a ligand stabilizes the receptor into the active state until the ligand and receptor disassociate. There's a lot of cool quantum effects and such if you really get into the weeds with some of the PPI theories.

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akwakeboarder t1_jbvgofi wrote

This makes a great deal of sense given that everything at that size/scale is moving and vibrating. Do you have a source for that model? I’d like to share with my students.

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hotlikewater t1_jbw003b wrote

Its the Cubic Ternary Complex model, you should be able to find some papers on GPCR activation for it that have SBML files you can download and play with

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brothersand t1_jbvy9za wrote

There's a book called Life on the Edge, by Johnjoe McFadden, that's about quantum biology. In one part he talks about evidence that the sodium pumps in neurons are so incredibly efficient because they somehow induce the sodium atoms to travel as waves rather than particles through their structure. It's incredible stuff.

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Thornwalker_ t1_jbtr07u wrote

Importantly, physical chemistry helped me to understand how protein protein interactions are essentially creating an energy 'well' that molecules and protein fall into.

It's why superoxide dismituase reached diffusion limited efficiency (let that boggle your noodle for a sec) whereas other more complex interactions are such that they occur less frequently.

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mikedensem t1_jbu7w6x wrote

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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horyo t1_jbukcos wrote

I find the lock and key mechanism to be a little bit more intuitive. A key (ligand) binds to the lock (protein/receptor) and a conformational change (unlocking) occurs.

For those other people who may also need ultra simplification.

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slashdave t1_jbvwn67 wrote

Not entirely accurate. Much of the free-energy of binding is related to entropy, depending on the ligand. A tight binding configuration, even with favorable energy, will not provide strong binding if it is not accessible (high enough favorable entropy).

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lernchecke t1_jbuca6e wrote

Is a competetive inhibitor the same as a competetive antagonist?

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123rune20 t1_jbulzlm wrote

Sort of yes. They both “block” something but inhibitor is often talked about in reference to enzymes while the latter is normally in reference to a receptor.

Competitive binding means it binds in the same place as the endogenous ligand.

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