Hello,
I have few ligands that I want to dock on an enzyme, but I cant figure out which docking scheme to carry on.
1) run an MD simulation of the holo enzyme, then dock on representative conformations from the trajectory. (based on RMSD clustering of the trajectory)
2) Dock on the enzyme, then take distinct binding modes (poses) for each ligand and use each pose to run an MD simulation in order to explore further conformational space.
3)Finally, Docking by MD, which is bit odd, but I want to place the ligand outside the pocket and then run an MD simulation and let the ligand dock on its own. (does that even work ?) (use only one copy of the ligand ?)
Thanks a lot.
Well, all three methods seem reasonable.
3 has the highest chances of failing and not giving you any useful data. I would not do that or leave it for later as the last instance.
2 is the most commonly used approach, if the xray structure of the receptor is known. If you know the binding site (which you probably do, since it's an enzyme with a well defined active site) you can use software which allows for flexible treatment of selected, active-site protein residues, like Glide or Autodock (not sure if DOCK allows that, older versions did not). That in some way simulates the conformational space of the protein, but obviously does not allow for major conformational changes, like 1.
1 is a good idea, particularly when using rigid docking scheme, but it's also more time-consuming than 2. But can potentially give you better answers, particularly if the conformation of the bound and unbound protein is quite different.
I would do 2, then 1 (or 2 and 1 at the same time).
Thanks alot !!
1 and 2 seems the most reasonable and the most common. I am doing 1 and 2 currently but if i were to do 3, do you suggest doing it with 1 ligand near the binding site ? or many ligands which are far away? a combination possibly ?
how far should should I place the ligand? I cant find much literature about it so if you have any suggestions I'll be glad to hear them.
You could take a look at Teresa Pisabarro's work on glycosaminoglycan-protein interactions for examples of 3. Good luck!
http://pubs.acs.org/doi/abs/10.1021/ci4006047
Dear Zaid Assaf, if you have reported crystal structure of your protein, then you can follow second scheme but if you don't have any crystal structure and you have prepared homology model of your protein then you can follow first scheme.
Third scheme seems interesting but i don't have any clue regarding the success or failure of the method.
Hi,
It is well-established fact that the PDB's have conformational and solvent errors. The benefit of MD simulations tools is to spot and fix the conformational problems. Moreover, simulations assist in capturing the mobility of proteins. Keeping these facts in mind, I would like to suggest scheme 1 and 2 . The third scheme seems quite interesting but, I don't think that this is gonna work as the prerequisite for the dynamics is the bound protein-ligand complex rather placing the ligand anywhere.
Hii Zaid Assaf
Check the mentioned link, maybe it will be helpful regarding your third query.
http://www.pnas.org/content/108/25/10184.full.pdf