Hi,

The question is yes and no simultaneously. As, the force field is not gonna describe better the protein binding site than the reality observed in X-ray. However, the "YES" answer comes when you analyze the electron density map and you observe the position of some atoms or amino acid moieties doesn't correspond to any density. In such cases, it would be worthy to minimize such atoms in order to achieve a better amino-acid orientation, but if the density is perfectly fitted to the protein coordinates, then, nothing special should be done, and,  therefore, no minimization should be carried out.

And for your second question why do you want to remove the metal part of a metalloprotein? The ligand may quite possibly interact with the metal part and if you remove that then there might be no interaction leading to false positive results. You will have to read the literature before considering any part. Hope this helps.

Regards,

Danish

Dear Danish

Thanks for replying me. Of course I have read articles. My protein is a metal carrier. I just have access to intact metal containing form but I need another one.

Dear Pritam

Thanks for your help. I don't know, why should I select the same position for the current docking process? I had said blind docking is the choice!

Hi,

If you remove the metal part of the protein you may loose the functionality of this protein or inhibitors which binds to it, for an instance in the case of carbonic anhydrase 9 you need the zinc moiety to be present so that inhibitors would have certain binding affinity to it. If you could tell me why you need another form of the protein then maybe we could find some solution to it.

And for selecting the same position (cavity) for docking as of the ligand which was previously bound to it , it's like when you don't have any idea about the cavity or active site or you don't know where your ligands should/would bind then it's good to go with the reference ligand in starting phase of the research. 

Regards,

Danish

Hi,

         All the above said suggestion are more useful in relate to docking. I would like to extend the clarification for why we choosing the same binding site for the new ligand in view of rigid docking. Mostly, this type of docking gives accurate interaction of ligands towards proteins.

        In general, the crystal structure has substates or ligands for making complex formation (furnished structure) and the native ligand has maximum binding affinity towards the binding sites of protein. So we could perform comparison between the other unknown ligands interaction and distance as that of native ligand interaction towards the same binding sites of protein.

      If we perform blind docking experiment, we need to study about the structural aspects of protein in specific to conserved site, hydrophobic binding pocket residues in receptor. then only we could identify in which binding site the ligand occupies and its interacting residues.

     In docking, optimization of ligand and proteins are very important step for making them as rigid or arranging conformers perfectly as compact structure. In some cases water molecules are helpful in protein ligand interaction study (researchers working on it).

Hope this points will help you to move next level.

Regards,

Rajesh

"How can i be sure that former changes which were caused by previous ligand couldn't mislead the new docking process?"

If there are several structures of your target, try a superimposition, and see which parts of your binding site appear flexible. Surrogate method (in case you have only one structure): look at SAR for existing ligands. Would your active molecules fit in the binding site, or would they require some changes in the protein structure in order to accommodate them?

"Is it necessary to optimize specially the protein structure before docking to avoid unfavorable changes, If yes, how can I do it?"

Difficult to tell. In some cases, it will not be mandatory, in some cases, it will. You might want to optimize the complex structure in order to remove some packing constraints or steric clashes in your structure. In come cases, some parts of your structure will be missing (e.g. some loops that could not be resolved) and you might want to rebuild them before defining your receptor. In most cases, I'd however keep a ligand inside, so to avoid collapse of your site.

"can I remove metal part of a metaloprotein then follow docking process without any optimization?"

If your metal is part of the binding site / catalytic mechanism, or is essential for structure intergrity, you should keep the metal. If your ligand aims to replace the metal, you should then remove it, otherwise, the ligand cannot bind during the docking run.

"why should I select the same position for the current docking process? I had said blind docking is the choice!"

If you already know what the binding site of your compound will be, it is a reasonable choice to define the binding site around the existing ligand (+ some extra space around it, obviously). I don't know what is the size of your protein, but blind docking against a large protein means a large grid. This might require you to select larger grid step size, and therefore to reduce accuracy.

Mr Vibhu kindly try SYBYL for this optimization.

Optimization is just for rectify the electrostatic interaction error, disturbance due to hydrophobisity , and confirmational entropy.

so my dear friend kindly refer following reference

Tortov M, Abagyan R. Protein- Ligend Docking as an Energy Optimization Problem. Drug - Receptor Thermodynamics . Page No 603-624.

I think This will help you vibhu.