I have an enzyme (human HMGCoA reductase) which has four active sites. The experiments had been carried out before from which IC50 values of several molecules were calculated. Now I'm about to carry out an in silico study so that I'll investigate their binding sites and mechanism. I know that I should keep the whole enzyme while doing molecular docking and molecular dynamics. However, I'm not sure which complex to go on with, e.g. molecule bound to enzyme's active site #1 or molecule bound to enzyme's active site #2? Is it reliable to pick the active site according to docking simulation, where the lowest-energy conformation binds?
I'm supposed to run MD once I pick a structure and do the analyses. I'll then draw some conclusions regarding the molecule's behaviour and interacting residues.
Before running any calculation, you must know well about the biology of the enzyme that you work on. Each active site is responsible for an individual biological activity. It's not a good start to think about which active site is suitable for your study.
You must know what you are looking from in silico tests on your system and must know which biological activity on the enzyme is your purpose to study on.
No one can suggest you to start your work from that active site and ignore the others, because no one is aware of your proposal you want to follow.
Are the active sites equivalent? Is the substrate binding cooperative? If nobody knows, consider all possibilities.
Martin Klvana the enzyme is a homotetramer and the active sites are identical. Not sure what you mean by "substrate binding cooperative".
Ramin Ekhteiari Salmas Thank you Ramin, I'm certain about what I expect from the in silico studies, but this knowledge doesn't quite guide me through the problem. All I'm sure at this stage is that it's an E.R-bound enzyme and I need to focus on regions which are not bound to E.R. Which exactly the pdb file I have comprises. It's a homotetrameric enzyme, so not sure about each active site responsible for individual biological activity.
If you need us to help you, you have to help us to understand your problem completely. You've not even talked which PDB code you are working on. You know your issue completely, doesn't mean that we know it as well.
Ramin Ekhteiari Salmas ok then :) the PDB code is: 1DQA. I'm supposed to bind several molecules that have similar moiety with that of statins, e.g pravastatin. I expect a good inhibition when it's bound to HMGR (1DQA). I'm planning to dock, run MD and maybe continue with QM/MM studies later on.
I think the following paper can be helpful on this issue that which active site can be used for clinical inhibitors.
Article Discovery of new druggable sites in the anti-cholesterol tar...
Please hold your horses; it's too soon to talk about QM studies.
Ramin Ekhteiari Salmas :) this is amazing but I was just reading this paper!
However, they seem to be more interested in the oligomerization mechanism (monomer-monomer interactions within the protein) and they aimed inhibiting exactly the oligomerization itself. But I'm digging and digging, maybe will find something useful.
Thank you so much though :)
Lalehan Özalp, if the binding is cooperative, the binding of the first substrate affects the binding of the second substrate . . .
Hi Lalehan Özalp
If you have four similar active sites, you can work on one. However, I am interested to know what you have decided?
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