Dear Radhika, terminal stacking is OK, why do you think there should be intercalation between G-quartets? We have never seen intercalation in modelling the binding of ligands to this propeller-type quadruplex (PDB 1KF!?). And we use QM calculations with full geometry and energy optimization, not just docking or MD.

The reason is that G4 is stable and highly optimized structure, and intercalation would strongly disrupt, deform and destabilize it. This destabilization is not compensated by the energy of new intercalating interactions. So the ligands prefer end-stacking or groove binding.

I don't see the structure of your ligand, but it is quite large (some metalloorganic complex?). And I agree with Dr. Domenico Sanfelice - your model is strange, the ligand is too far away from its target, and perhaps there are no aromatic stacking interactions. What are those green bonds from your ligand? But in principle docking is too approximate tool for the serious study of complex interactions... It may be useful to some extent for mass virtual screening, but not for structural studies. I, personally, avoid this approach. 

Dear Radhika, probably Autodock Vina is not the best software to solve your problem.

If you want your ligand to intercalate between the stacking bases you should allow the bases to be flexible in order to allow you ligand in. I know that Vina has the possibility to allow flexibility of protein side-chains, but I don't know it that's the case with DNA bases. One additional comment: the docked ligand is not correct! You should expect the aromatic region to form stacking interactions between ligand and receptor: that will make much more sense. Best of Luck for your simulations

Dear Dr. Domenico Sanfelice,

Thanks for the suggestion. I will try to do it in some other software.

With regards,

R. Radhika

Dear Lalit,

Thanks for it.  I Will try that to get the good results.

Dear Radhika, terminal stacking is OK, why do you think there should be intercalation between G-quartets? We have never seen intercalation in modelling the binding of ligands to this propeller-type quadruplex (PDB 1KF!?). And we use QM calculations with full geometry and energy optimization, not just docking or MD.

The reason is that G4 is stable and highly optimized structure, and intercalation would strongly disrupt, deform and destabilize it. This destabilization is not compensated by the energy of new intercalating interactions. So the ligands prefer end-stacking or groove binding.

I don't see the structure of your ligand, but it is quite large (some metalloorganic complex?). And I agree with Dr. Domenico Sanfelice - your model is strange, the ligand is too far away from its target, and perhaps there are no aromatic stacking interactions. What are those green bonds from your ligand? But in principle docking is too approximate tool for the serious study of complex interactions... It may be useful to some extent for mass virtual screening, but not for structural studies. I, personally, avoid this approach. 

Dear Dr. Igor Dubey,

Thank you so much for explained me about the terminal stacking in this case. Actually I am also going to use QM calculation only. Still I wanted to check the conformer. So only I have done docking. That Green colour bond is an hydrogen bond between ligand and DNA. Herewith I have attached the docked conformer for your reference, Can I get your kind assistance in this issue?

With regards,

R. Radhika

Dear Radhika,

Now I see from your pdb file that you use a limited telomere/quadruplex model consisting of 2 G-quartets (not 1KF1 quadruplex), and you try to form its complex with thiodeoxyguanosine. At a first glance, it seems quite realistic, although binding energy will be probably low. Well, how could I help you with that?

Igor

Dear Dr. Ignor Dubey,

I want to know whether this is a good starting point for the QM calculations or have to try it with some other docking software to provide the more realistic starting structure. I need your kind suggestion in this issue.

Sincerely,

R. Radhika 

Dear Radhika,

I don’t think that you need other docking software to start with QM. The structure of your complex already seems to be realistic as I have told you. The position of heterocycle is OK, it is coplanar with G-quartet, and the distance between them makes it possible to form stacking complex. Sugar residue forms H-bonds with a quartet. I would not say that this structure is too strange or impossible (but I don’t say that it is the most energetically favorable one, you cannot get this with docking). I think that you can start QM here, and optimization procedure will probably lead you to some local, or even global, minimum. However, you should understand that you use a simplified model of quadruplex, so your computation results (even 100% correct for this model) may be far from the real geometry and energetic parameters of ligand complex with telomeric G4. The binding of your ligand is probably weak since purine heterocycle is too small to form efficient stable stacking, and it is neutral (uncharged). By the way, have you first optimized the structure of your ligand? Is it really in syn conformation? It is possible of course, but usually anti conformation is favored for purine nucleosides.

Igor     

Dear Dr. Ignor Dubey,

Thanks you so much for the valuable suggestions. Actually I have not optimized the drug yet, but I have extracted it from the pubchem. The reason for selecting the above model is, computation cost of QM calculation is so high for the real model. So I have simplified it in the above way which is in agreement with the recent literature survey..

Sincerely,

R. Radhika

Sure, your model is good and much better than just an isolated quartet. We currently use for QM full quadruplexes Tel22 of various topologies, and indeed non-empirical QM takes months. But semi-empirical approaches like PM7 are much faster (1-2-dys for one ligand on our resources), and the results are usually more-less adequate (not always). Good luck!

Igor 

Thank you so much Dr. Ignor Dubey, I will do it using ONIOM ,which gives considerable accuracy with low computation cost. All the best for your research..