Submitted by Eat-A-Torus t3_11oij2y in askscience
So the sort of thing that instantly comes into my mind is like a key fitting into a lock, or like a puzzle piece connecting with a neighbor... But the scale is far too small for those sorts of concepts of rigidity or even solidity, right?
There are two functions happening usually: Binding and Activating, for an agonist.
For an antagonist, you'll have Binding and Blocking. Usually you'll have a greater binding affinity for antagonists that can knock an agonist off of the receptor.
I know you're mentioning messenger proteins, but a chemical example is how Naloxone will knock off morphine from a receptor due to its higher affinity. The naloxone then blocks morphine from activating the receptor.
When an agonist binds, it can change the channel's confirmation allowing influx, or efflux of ions. Depending, this can increase or decrease the chances of an action potential to occur.
Sometimes things get even more complicated. The chloride channel that Valium works on, the GABA receptor, has receptors for GABA and receptors for benzodiazepines (valium-type drugs).
One single channel, or one single neuron may not play a large role, BUT..., When hundreds and thousands and millions of receptors and neurons are affected, you see an overall effect in the subject.
Addition: sometimes, the receptor might not do something directly. Instead, it activates second messenger (intracellular messenger) that may do something, e.g. like what you found on GPCR.
Actually, when you're at the scale of these molecular interactions, the concepts of rigidity hold up pretty nicely. (BTW, the broadest term for these kinds of interactions can be called "ligand-receptor binding", and the "lock-and-key" model works well for describing it. The ligand (or soluble protein) binds specifically to its receptor with high affinity. The subsequent steps are analogous to the mechanism within a lock when the key is turned. The altered structure of the receptor causes a change in another molecule (e.g., a "kinase" enzyme), which in turn induces a conformation change in another molecule. Subsequent interactions can result in a cascade of changes that result in the cell changing in some way (e.g., secreting a hormone or altering the voltage potential across its membrane).
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.
In short, when the ligand (can be peptides, drugs, proteins, etc.) binds to receptor, the said receptor will change its form ("conformational change") and allowing some kinds of actions, i.e. opening ion channel, releasing some kinds of intracellular molecules (second messenger system), increasing/decreasing transcription of some genes, etc.
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Some ligands can be highly specific to its receptor, but some ligands may act at many different receptors. The ligands can bind irreversibly or reversibly, allowing different duration of action and concentrations affecting how the receptor works. Some ligands may also compete for same space of receptor, allowing it to act in dose-dependent manner.
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References:
Katzung BG. Basic and Clinical Pharmacology. 14th ed. New York: McGraw Hill Education; 2018.
Whalen. Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) SEVENTH EDITION. Vol. 53, Journal of Chemical Information and Modeling. 2019.
Often you will get a conformational change in the receptor upon agonist/antagonist binding. So, the bound compound changes the electron distribution of the receptor just enough that it's more stable in another state. For AMPA receptors, for example, they're composed of 4 proteins that form, like, columns through a cell membrane. When it's not activated, the 4 proteins are slightly twisted, such that there is no opening between them. With each glutamate that binds, the proteins that make up the AMPA receptor twist slightly, exposing an opening down the middle. The more open the receptor, the more ions can flow through the channel. When an antagonist binds, the quaternary structure of the AMPA receptor is more stable in a deactivated state, even if more glutamate bind. These bindings are typically transitory, so the molecule will kind of "flicker" on and off the receptor, but when concentrations are high, it's more likely to be bound, and when concentrations are low, it's less likely to be bound.
TL;DR: It's about electron charge distributions.
Proteins can* be very rigid, and that rigidity comes mostly from four forces:
hydrophobic and hydrophilic interactions (some amino acids will stay away from water and twist to the inside of the protein, others will be attracted to the water and be on the outside of the protein)
hydrogen bonding in the protein (some substituents make strong dipole interactions with each other, these forces also exist in the backbone of the protein, making sub-structures)
electrostatic interactions (parts of the protein carry positive and negative charges, which help hold the protein together)
disulfide bridges formed from two cysteines which are actual covalent bonds between two parts of the chain
Here's the important part: when something binds to the protein, the electrical and chemical environment around the protein changes, and the protein will* change shape. For example, if a signal peptide with a lot of charged side chains lands on the receptor site, amino acids with charged side chains in the receptor will try to twist towards or away from it. This will change the shape of the protein, potentially opening new receptor sites or setting off other signalling.
A great example is this animation of a G-protein coupled receptor. Watch it change shape as things bind and unbind to it (the good part starts at 4:15) https://youtu.be/ZmrDWIeX0Tc
*Per /u/danby, below, the hydrogen bonding network is quite flexible, so we can't really call the protein a rigid body.
*Again, per /u/danby, there are examples of binding without structural change.
It's like i learned more.. but know less?
>Actually, when you're at the scale of these molecular interactions, the concepts of rigidity hold up pretty nicely. (BTW, the broadest term for these kinds of interactions can be called "ligand-receptor binding", and the "lock-and-key" model works well for describing it.
That is not true. The lock and key model is known to be less correct than models such as induced fit or conformational selection.
For understanding the idea the lock*key model works very well I think. I mean, it gets hard if you take into acount that most ligands don't bind covalently and attach/detach based on chemical properties that we -for simplicity's sake- call affinity. It brings in a lot of very specific kinetics that aren't usefull for understanding the basic concepts.
If OP goes deeper into biochemistry those factors will start to play a role and will be introduced bit by bit to keep it doable. A reddit post isn't really the place for that level of detail imho.
Static cling is part of it
Amino acids are arranged in a 3d matrix that creates a patch or a pocket with a particular pattern of positive and negative charges that complement a pattern of charges on the other molecule (the ligand). There's are also interactions involving hydrophobic vs hydrophilic molecular affinities, as well as overall physical shape.
When binding occurs, the interactions can induce changes in the overall shape of the binding site, as these different charges are "neutralized" against each other, or the two molecules adjust themselves for a better fit. This can sometimes result in the exposure of and otherwise hidden amino acid that can cause some further interaction to occur. There are also ways in which an amino acid nearby in the structure might pull electrons away from some part of the ligand, changing the properties of the molecule in a way that might cause it to break a bond. Breaking the amino acid chain in the ligand can then cause the other interactions holding it to the receptor to change, making the two parts no longer compatible with the receptor, allowing it to release .
I am leaving a whole lot of stuff out, but this is an idea that I find to be easier to visualize .
There are some types of locks which use and arrangement of magnets. The north and south poles of the different magnets are set up in a pattern that is complementary to the arrangement in the magnetic key. And so when you put the key next to the lock it can open, but if you put the wrong key next to the lock it will not be able to bind correctly. This is actually not a bad way to look at the interaction of receptors and their ligands or enzymes and their substrates.
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Induced fit or conformational selection seems to be the two explanations with the most backing.
In induced fit, binding of the ligand changes the shape of the protein.
In conformational selection, the protein samples a number of different shapes, a subset of which is compatible with ligand binding.
I tend to think that "induced fit" is essentially conformational selection. All molecules seem to "breathe" to an extent, ie. small-scale movements between atoms (you can see this on structures in PyMol by looking at the B-factor) so this makes the most sense.
The best model I’ve come up for it, is to imagine how helpful it would be if locks attracted the key that could be used to unlock them.
Because the scales are so small, the charge amounts for the attraction and repulsions are minute, but real.
Granted, I’m self taught on all of this, so there will likely be objections to this simplification, but at the end of the day, it’s all about moving electrons around.
I've been quite enjoying these very short "nutshell" explanations of all sorts of science topics. They simplify and barely scratch the surface but give you a hint that you can follow up on. All of them are quite fun: Kurzgesagt The Most Complex Language in the Universe https://youtu.be/TYPFenJQciw
Lots of good answers already, so I'm suggesting a couple of resources instead of answering. Check out the protein database to see the different known shapes of proteins: https://www.rcsb.org/ This is a bit old, but here is a talk about visualizing protein dynamics: https://m.youtube.com/watch?v=t3uQDL-GdLM.
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I don't think we'd regard proteins as rigid bodies. Lots of what makes working with protein structure hard is that we don't have a good way of modelling the dynamics of proteins. The hydrogen bonding network is quite flexible.
Ligand induced structural change is indeed an important type of ligand binding but there are many examples of binding without structural shifts.
Here’s hoping for further developments with cryo-electron microscopy. The largest benefit imo being it doesn’t require lengthy crystallization waiting periods.
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.
Good addition, I'll add a clarifying note to my post. I have a neuroscience background so all the receptor stuff I learned about was based on structural change.
To add to this, there’s an iterative set of interactions where ligand binding induces conformational changes on the receptor, which induces some conformational change on the ligand, and so on. That’s why in silico docking that assumes a rigid receptor often gives spurious results that don’t line up with experimentally measured binding affinities. It’s problematic since reductions in receptor degrees of freedom can impose a significant entropic cost, which can have a major influence on the Gibb’s free energy of the binding event.
We’re getting better at modeling those interactions than we used to be, but it’s still extremely challenging. The best efforts start with a large collection of known binding affinities with different ligands, which can be used to constrain the system.
Great addition?? Thanks.
A big issue is the lack of data. There are lots of crystal structures of proteins and lots of structures with ligands bound but very little data of the intermediary states along the way to binding.
The flash freezing certainly/hopefully offers a path to capturing many intermediate states for proteins as they Bind small molecules
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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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Is a competetive inhibitor the same as a competetive antagonist?
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.
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.
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.
Got it. Thanks!
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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.
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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From memory, organic molecules have rigid structures but also bonds that rotate so macro-molecules can changes shape to envelope a ligand. This is sometimes called the induced-fit model. My general conception of which is a bit like a catcher's mit.
Because of thermal energy equilibrium, a ligand is moving much faster relative to an enzyme. So it'll arrive at break-neck speed and smack into the catcher's mit and then probably bustle around a bit. The ligand and its associated water bubble (closely interacting water molecules) will interact with arms of the enzyme, attracting them to move and grasp the hydrated ligand. Eventually this movement will displace the water molecules, leaving only the chummy direct embrace occuring between the ligand and the protein. They are compatible and decide to make a night of it. So the big one is hugging the little (or the mit is holding the baseball). At this point my dualing metaphors break down because they interact chemically, often with the help of a phosphate molecule to power the little (nano) machines into doing some metabolic magic.
They then decide that they need some time apart to get their heads straight and find themselves, leaving only an ambivalent ADP molecule looking on as they make their separate ways in the endless hustle and bustle (thermal agitation) of the molecular realm.
My metaphor of the catcher's mit seemed to metaphorphose into more of a romantic interlude but you get the idea. Molecules in this situation are basically like ravers in a mosh-pit who are attracted to one another, hug, make out briefly, then realise that they have to find their friends.
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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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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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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Your instinct is correct that the physical metaphor is wrong. Proteins are not as solid as a lock and key. Also, a lock and key relies on physical shape. Protein protein interactions rely on shape +intermolecular forces.
Molecules have slight positive and negatively charged areas on them. Single bonds can rotate more or less freely assuming the parts they are attached to aren’t too big and hit each other. So it’s almost like they are slightly flexible magnetic rotatable chunky things, and the way they fit into a receptor, (also a chunky magnetic flexible thjng) is by their positive and negative areas matching up with negative and positive areas of the receptor.
It sounds like it would take forever, like it must take so much vibrating around for the exact molecule among millions to slot into place, but molecule speeds are insane, they move FAST. There are enzymes that can grab a molecule, break it apart, let the pieces go, and repeat with s new one…60,000 times in a second.
Lol I tried to make a quick answer ha
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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.
>But the scale is far too small for those sorts of concepts of rigidity or even solidity, right?
No, atoms are solid, and the bonds in the molecules are usually quite strong. The lock-and-key analogy is not very good, however. For one thing, molecules and proteins are not rigid. And the binding is a statistical process. It's just that the protein and molecule prefer (by favorable energy and entropy) to be together then apart in solution.
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).
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).
Molecular dynamics is adequate in most simple cases. You could say we are limited with what kind of computing power we can apply in complex systems.
The intermediate states are irrelevant. It is only the free-energy difference of the two states (bound and unbound) that matter.
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.
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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They are far far far more complicated than you would expect if you’re thinking it’s small so it’s simple. A lock is far simpler than a protein. Part of this is due to lower rigidity. Part of the proteins structure is well… structural. They need to be complicated to maintain structure.
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Why on earth would we be only interested in simple cases?
MD is fine in many cases (very, very good in some) but it is absolutely not sufficient to fully model and understand the dynamics of proteins. We know the forcefields we have are lossy and not great for many applications when it comes to proteins. Simulations of long time spans or large protein rearrangements are generally very poor.
> You could say we are limited with what kind of computing power we can apply in complex systems.
Well yeah we limited there.
> The intermediate states are irrelevant
Irrelevant to what? They seem pretty relevant if we're studying protein dynamics.
> It is only the free-energy difference of the two states (bound and unbound) that matter.
It's the only information that matters to what? If we're studying protein dynamics can you predict if a protein undergoes a change in structure form the change in free energy alone?
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>Why on earth would we be only interested in simple cases?
We aren't. The statement "we don't have a good way of modeling the dynamics of proteins" isn't correct. If you want to amend that to "complex systems", you might have an argument, but there are also accelerated MD methods that are quite effective.
how are they solid? I thought most of a molecule is empty space, with little bits of solids protons/neutrons in the nucleuses, and the electrons diffused in a cloud around them?
Atoms repel each other quite strongly using what is described as "Van der Waals" forces (electrostatic in nature). The length of bonds between atoms are relatively inflexible and keep bonded atoms close enough to prevent other atoms from slipping between.
For example, proteins often fold around and trap water molecules within their structure. Many of these water molecules remain trapped until the protein decays.
TheDungen t1_jbspteo wrote
It's more that a certain number of postive centres at a certain distance line up with a number of negative centers at the same distance but, there is definatly the fitting part too proteins fold certain ways and are generally stable unless denatured.There is also the fact that a particle can be Sterically hindred so that there are directions it cannot bond from because of other groups blocking.They don't fit at puzzle pieces but as semisolid clouds of matter where one part of one molecule needs to be the right size and align properly with the right groups on the other molecule.