I am trying to dock ligand to a homotetrameric protein which is functional only in its tetrameric form. My problem is I have to dock four ligands in the four catalytic pockets of each monomer. Please suggest a good method or servers for docking multiple ligand docking to the homotetramer.
There is no such thing unfortunately, but it doesn't seem like you're gonna need to do so, at least so I believe. Because it won't make any different, you see, in docking the protein is almost completely rigid (I said almost, because some docking tools allow certain degree of residue flexibility around the binding site), there will be no change in the overall protein structure.
If you would like to see how does the tetramer behave when the ligands bound then what you need is a molecular dynamics simulation. But there will be an additional problem if the ligand is not one of the common biological ligand (e.g. ATP, sugar, etc.) since you need to parameterize the ligand prior the simulation.
The best and most practical strategy I can offer is to use the protein structure in PDB with tetrameric form and bound to a ligand that have the similar behavior to your ligand (inhibitor, agonist, antagonist, etc.), that way the protein structure will be more accustomed to the ligand that you're about to test. Check the paper below to see what I mean. Then choose one of the monomer (the four of them most likely completely identical) and use it for the docking simulation.
Article Selective Structure-Based Virtual Screening for Full and Par...
One way you could do it, is perform the docking four times, once on each pocket respectively. You can make multiple copies of the ligand with different names to distinguish it more easily, though that shouldn't really be necessary. Just change the definition of the docking site between each round.
Hi, I am not aware of any tool that will allow you to perform docking in four different binding sites simultaneusly.
If the protein is homotetramer I think you can safely perform the docking using the minimum system that defines your binding site (that can be a single monomeric unit but often the binding site is at the interface of two monomeric units so two units would be required to define the binding site).
Most likely the four binding side will not be identically (even if all four of them have the same ligand bound or are apo). An analysis of the four binding sites (by superposing all of them) could give you an idea of the portions of the bbinding site that can be flexible or side chain that can adopt different positions. Typically in PDB structures chain A is the higher quality part of the structure but that need to be verified.
Another option, probably the most interesting one, would be to consider the four binding sites as separate structures and treat them as different conformation of the same complex to perform ensamble docking.
Docking to an ensamble of conformations or structures of the same protein bound to different ligands normally leads to better docking results. There is plenty of literature out there about this. Just as an example please look at the CCDC document "Improved docking performance using ensemble docking" (link below).
The docking software GOLD (again by CCDC) has in-built module that will allow you to deal with ensamble docking (see link below). Other software will also provide similar facilities (Glide is Schrodinger for instance).
Hope this helps
Best of luck
http://www.ccdc.cam.ac.uk/Lists/ResourceFileList/ensemble_docking.pdf
http://www.ccdc.cam.ac.uk/Solutions/GoldSuite/Pages/GOLD.aspx
Ah right, I forgot this one. As Fabio mentioned above there are multimeric protein that can be inhibited through interaction at the interface site. One of the example is attached below.
Article Inhibition of a Viral Enzyme by a Small Molecule Dimer Disruptor
Thank you for all the suggestions. I will be trying ensamble docking. Also I am trying to do interactive docking,in which we superimpose the known structure with the docked ligand with the target and then remove the template chain. so we now have the ligand with the target.
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