How does chemical structure correlate with protein structure and binding?

[Streetcow]

The title says it all

iv had an ENORMOUS struggle to try and figure this out (36 hours and counting of research that hasn't turned up anything except cell signalling and signal transduction)

so I thought I would bring it to the forums to see if anything knew anything

All answers are appreciated

-Streetcow

 

[Solipsis]

Chemical structure of a receptor ligand, or of proteins in general?

If the latter, then it is called tertiary structure, which determines folding: the amino acid sequence in very complex ways causes the protein to be tangled up into lumps, helices and sheets, and often combinations of such structures.
How it works basically is that a protein is first and foremost a chain of amino acids which have residues hanging off of the sides of each link, and those residues can hook up to one another in pairs. Unlike the regular pattern of pairs in DNA, protein amino acid residues combine much more 'chaotically', but also with method to the madness. Irregularly, but making exact matches in order to get the right tangle to produce functional proteins / enzymes.

If the former, then it is the amino acid residues that hang off the amino acids that are exposed on the 'surface' that are left over and do not pair to make the tertiary structure of the protein, which are able to interact with ligands. The ligand is like a key fitting a lock, with specific chemical structure and properties (shape and electronic / polar or non-polar groups at particular positions). The shape fits the shape of the protein AND the groups hanging on the outside of the protein match the ligand's in such a way that there is pushing, pulling and binding. This causes a leverage which triggers a change in the way the protein is folded with all sorts of consequences, like making it detach a part of it or opening up a pocket on another side where other ligands can act - it can cause many mechanical, electrical or enzymatic events.
In the case of receptors, it can cause activation of the receptor if bound right... which triggers chemical signals to be sent on the opposite side of the receptor protein, which lies on the other side of a cell wall barrier, where messengers propagate the signal and/or polarization changes of the neuron are effected by IIRC flux of ions through channels.

But correct me if I'm wrong.

 

[belligerent drunk]

I'm assuming that you're asking why certain simple, non-polymeric organic compounds bind to receptors (which are proteins/polymers) and produce a "signal"? A simple explanation would be to say that electron density and steric factors play the most important roles. Non-covalent (no chemical bond is formed) binding typically occurs due to van der Waals forces, like the polar-polar, polar-induced polar, and dispersion forces, and hydrogen bond being another very important factor. For example, non-protonated aniline's nitrogen's electron pair would interact considerably with phenol's oxygen's hydrogen (acidic hydrogen), forming a hydrogen bond. Or two benzene molecules would interact with each other's slightly more polar electron structures than cyclohexane, for example (benzene having a weak negative charge above the plane of the carbon atoms - benzene being planar - and slightly positive charge at the hydrogen atoms; this not being the case in cyclohexane, which is perfectly apolar as far as that is concerned)

E: Solipsis explained it very well as far as the receptor protein is concerned. In this case, the ligand, as I described, binds to the receptor by the way of vdW forces, and that binding results in the receptor protein changing shape/behaviour resulting in secondary signal (like cyclic adenosine monophosphate) being sent inside the cell.

 

[Streetcow]

Thank you both for answering my question and taking interest in my thread

though while you gave a more complete response (thank you for that) it means I should have been more specific I'm wondering how exactly does the key and lock idea with ligands and proteins work? I know it's more complicated than just a key fitting into a lock after all protein are flexible and more complex

im also wondering how the helix structure of showing proteins works and where in the structure do the Ligands bond

-Streetcow

 

[Nagelfar]

...The ligand is like a key fitting a lock...

But correct me if I'm wrong.

... I know it's more complicated than just a key fitting into a lock after all protein are flexible and more complex...

Read up some on "induced fit hypothesis" as it contrasts to "lock and key hypothesis", it is likely that the truth is somewhere in-between (depending on the atomic make-up of adjacent heteroatoms, some are a measure more rigid with strict requirements and some changing the configuration of the receptor site to adjust to the ligand itself, altering the allosteric criteria for binding); but the former hypothesis makes me conclude that it, in it's case, can explain the observation of "super-agonism" for some exo-genous ligands (i.e. induced fit)

 

[Streetcow]

Read up some on "induced fit hypothesis" as it contrasts to "lock and key hypothesis", it is likely that the truth is somewhere in-between (depending on the atomic make-up of adjacent heteroatoms, some are a measure more rigid with strict requirements and some changing the configuration of the receptor site to adjust to the ligand itself, altering the allosteric criteria for binding); but the former hypothesis makes me conclude that it, in it's case, can explain the observation of "super-agonism" for some exo-genous ligands (i.e. induced fit)

man this is a complicated topic

I'm trying to fully understand this so I can utilize this for drug design and figuring out unknown variables in drug binding based on certain receptors but it looks like its gonna take awhile to integrate because based on what the receptor protein will bind to and what the structures it will bind too it is very very specific and complicated

I think (but correct me if I'm wrong) you could design drugs to target specific receptors and get EXTREMELY precise effects from a very advanced knowledge on how this works and get specific results like pain relief,deep sleep, or anxiety relief without the dangers of regular drugs on the market such as benzo's with
addiction,receptor destruction and the like

-streetcow

 

[belligerent drunk]

though while you gave a more complete response (thank you for that) it means I should have been more specific I'm wondering how exactly does the key and lock idea with ligands and proteins work? I know it's more complicated than just a key fitting into a lock after all protein are flexible and more complex

Are you familiar with how inter-molecular forces work? For example why hydrophobic compounds tend to stay with each other, while hydrophilic compounds keep together instead. The most fundamental reason for things such as that is energy - what is most favorable. If a compound (say, a receptor ligand) is able to interact with its "target" (a receptor) in such a way that it is favorable for the compound to be in a particular space within/close to the repector, you may assume that it binds to that receptor.

As far as that goes, the key and lock explanation works pretty well, because the electron structure of the ligand has to match the electron structure of the receptor/protein, in such a way that their binding is energetically favorable.

I'm trying to fully understand this so I can utilize this for drug design and figuring out unknown variables in drug binding based on certain receptors but it looks like its gonna take awhile to integrate because based on what the receptor protein will bind to and what the structures it will bind too it is very very specific and complicated

Are you saying that you work in making drugs? Because if that's the case, then I'd imagine that you'd be very familiar with the structure-activity relationship (SAR) concept. Anyway, once you get around to understanding the basic concepts of inter-molecular interactions, it should be no problem understanding how everything works.

I think (but correct me if I'm wrong) you could design drugs to target specific receptors and get EXTREMELY precise effects from a very advanced knowledge on how this works and get specific results like pain relief,deep sleep, or anxiety relief without the dangers of regular drugs on the market such as benzo's with
addiction,receptor destruction and the like

Yes and no. If receptor proteins differ in their electronic structure at the binding site, then in principle you could design different drugs with very good selectivity, but there are certain limitations to that. First, receptors of the same class don't always differ enough; and second, the choice in organic molecule's electronic structure is often not intricate enough to allow for very fine tuning.

 

[serotonin2A]

There are many good papers that have been published where groups have worked out why a particular ligand binds to a protein. For example, here is a recent set of studies published for the dopamine receptor:

http://www.ncbi.nlm.nih.gov/pubmed/25970245

In terms of doing this yourself, you are not going to be able to model the interactions accurately unless you receive intensive instruction/training by someone who really knows what they are doing. There is a reason why people go through the trouble of getting PhDs in this field. It is not necessarily difficult to go through the steps to generate a model and then perform simulated docking studies. But what is difficult is doing those procedures correctly so they yield accurate results. There are many steps involved, each of which requires multiple decisions that can potentially make the results diverge from reality. It also helps to have a good background in pharmacology and physical chemistry.

 

[Streetcow]

There are many good papers that have been published where groups have worked out why a particular ligand binds to a protein. For example, here is a recent set of studies published for the dopamine receptor:

http://www.ncbi.nlm.nih.gov/pubmed/25970245

In terms of doing this yourself, you are not going to be able to model the interactions accurately unless you receive intensive instruction/training by someone who really knows what they are doing. There is a reason why people go through the trouble of getting PhDs in this field. It is not necessarily difficult to go through the steps to generate a model and then perform simulated docking studies. But what is difficult is doing those procedures correctly so they yield accurate results. There are many steps involved, each of which requires multiple decisions that can potentially make the results diverge from reality. It also helps to have a good background in pharmacology and physical chemistry.

well the thing is I don't have much money

im a small time "pharmacist" that sells semi legal (but safe and mind blowing all are tested on the good ol human Guinea pig know as myself) designer drugs

and also drugs I can get away with in canada (here codeine cough syrup is OTC if you get what I'm saying its also a good model to work with when developing opioids)

I also develop my own chemicals that I test and sell to my "clients"

Right now I'm getting over a full blown heroin addiction so there's that also and since most of my money goes to my personal lab, the internet,drugs and music i have to tough up and learn everything I know online

so im in no position to go back to college (was a disaster last time I got caught with pure morphine and to make matters worse I was mid shoot when a teacher just happened to find me)

but if you could lead me to online course I might be abled to take that would be AMAZING and I would be forever grateful (if its worth anything on the internet)

I already know a great deal but like I have said before I'm an intermediate chemist and looking to become advanced I still have much to learn

thanks though on the PHD suggestion it just not happening right now

-Streetcow