Hi
For validation of docking protocol usually dock again co-crystallized ligand in protein, and if the same conformation with acceptable RMSD reproduced, this setting use as protocol (setting) for docking other ligand in virtual screening or ... .
Most of the software can consider water molecule in docking process but considering the water molecule in active site has difference effect on docking result and docking score,so for reproduce experimental result ( ligand pose and conformation by docking as guarantee for validation of docking setting) i must consider water molecules in active site or not?
because when i consider water molecule in active site in Gold and flexX i gave different conformation from reference ligand in protein complex.
Best regards,
Mohamad
Hi,
You should try to estimate binding free energies of each docking pose by MM/PB(GB)SA method implemented in AmberTools, which gives more reliable results for ranking the poses.
AmberTools is free.
http://ambermd.org/#AmberTools
http://ambermd.org/tutorials/advanced/tutorial3/
agreed the superimposition of the native ligand and the docked ligand being processed by you, confirms the docking protocol to be suitable and accurate, with a low r.m.s.d value.
Try to remove non-interacting water molecules first, then remove all water molecules. Compare docking pose with crystal ligand in both cases. A docked pose with RMSD
Thanks Dears
By recommendation of Mr. Mishra i got RMSD=1.206.
But i have other question about ligand minimization before docking?
We have many method for minimizing molecule like Force field , Semi-imperial , Ab initio QM , QM-MM , but we must chose which of them and why?
for example i select OPLS in GLIDE and minimize molecule with flexible cyclic (this method consider ring as flexible) but i cant dock this molecule in FlexX (docked with no result).
I ask this question in past but no one cant answer my question with strong reason, so i wanna know that really we have standard protocol for minimizing ligand before docking for use in different program?
Best regards,
mohamad
Thanks Elvis
Really in my perspective optimizing ligand for docking its usefulness job because in the most of the docking software, searching algorithm search in many conformation of ligand for best pose or conformation for active site not best minimize conformation, but in another way we do optimization for bond length or ... .
Totally its unsolved issue and most of docking paper don't mention any thing about it.
and my name is Mohammad ,not mohd.
Thanks all.
Best wishes,
Mohammad Akbari
Hi dear Paul
at the first thank you for answer, but about your first paragraph, I have different point of view!
In the past I have same opinion but know I'm sure that the optimization of ligand have important effect in docking result because I test it. and about your last paragraph I think that the solvation parameter or solvation terms added to scoring function.
Best regards
Mohamad
The molecular docking protocol was validated by re-docking of the co-crystallized ligand back into the same active site of protein and found to follow the same interaction pattern and results. The docking of co-crystal ligand against the generated grid showing exactly same docking mode and interaction such as hydrogen bonds as your molecule with RMSD value of less than 2 Å (good) and therefore, docking protocol was validated by the generated grid. The success rate in retrieving binding modes of known protein–ligand complexes is an important validation for docking programs. The measure that is usually used to determine whether a binding mode prediction is a success is the RMSD. One generally considers an RMSD < 2 A as a successful prediction.With larger deviations, many of the observed interactions between the protein and the ligand will not have been predicted correctly. The current availability of protein–ligand complex structures provides opportunities to construct data sets needed for large validation studies to evaluate and improve docking methods. In validation studies, a library of decoys is usually enriched with known inhibitors of the target from the literature can be consider.
It is totally your call whether to keep water molecules in the binding site or not. Some ligands may compete with waters and oust them from the pocket. Others may use waters as a part of the binding site. You should also keep in mind that many of those water molecules' positions have not been determined with high confidence.
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