positive binding energy problem

[tanver hasan]

no matter which method I perform I always end up receiving a positive binding energy. 

I have tried C2_entropy, Interaction Entropy. 

And since I have used charmm36 force field I can not use N Mode. 

I have even changed some parameter 

igb=8 

intdiel=8

The trajectories frame that I have chosen for the simulation are quite stable.

But still getting positive energy.

can anyone please suggest how can I solve it ?? 

[Mario Sergio Valdes]

Please, share the output file to check the energetic terms

[gmx_MMPBSA]

Those entropy methods have disadvantages, one being the need for extremely stable simulations. That being said, it's not surprising that the authors of the methods used restraints in order to get extremely stable interaction energies. The thing is that the entropy calculated using these methods quickly diverges in not-so-stable simulations where you have a considerable variation in the interaction energy. You can find more information in this paper:

https://pubs.acs.org/doi/full/10.1021/acs.jctc.1c00374

[tanver hasan]

here are the output files generated for two separate docked complex.

[tanver hasan]

Can you please tell how can I solve this problem ?

[gmx_MMPBSA]

As I see in your files (although the standard deviation of the interaction energy is not the worst I have seen, still is not optimal below 3.6)... Even more concerning is that the enthalpy of your complex is quite low... did you check the trajectory? does the complex remain stable? which interactions are predominant in the interface?

[tanver hasan]

yes . I have used the last 1000 frames. And from the RMSD It is evident that they remained stable. there were conventional hydrogen bonds ,carbon hydrogen bonds present. 

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[Mario Sergio Valdes]

The enthalpy contribution is quite low. The complex interaction could not be favorable. Can you share the complex structure?

[tanver hasan]

Here are the complex files. Do I have to upload the complex.gro files ? 

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[Mario E. Valdes-Tresanco]

Checked your files and everything seems fine... how about the relative binding free energy, is it expected to be ~2kcal/mol between imperialine and jervine? Usually, this method is not as good at reproducing absolute as it is at reproducing relative binding free energies...

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[tanver hasan]

I did not understand your question.

But my concerns still remain .

is it possible to report the actual binding free energy ?

I can not solve the problem of getting positive values, no matter which method I apply. 

[gmx_MMPBSA]

Seems in this case the method is not able to recover the absolute binding free energy... But what you can report is the relative binding free energy (that will be DDG = DG imperialine - DG jervine for example) and compare ut to the experimental DDG value

[tanver hasan]

Jervine and imperialine are two separate compounds. And they have been docked with the same protein . So you want me to compare between these two compound energy ? 

And in the command line it was recommended to use reference .pdb structure . I am not using them. Using them can help me to get a better results ? 

And it was also mentioned that Hydrogen should not be present .two complex files that have I sent few days ago will they be okay to work with in this regard ? 

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[Mario E. Valdes-Tresanco]

Jervine and imperialine are two separate compounds. And they have been docked with the same protein . So you want me to compare between these two compound energy ?

Yes, in fact this is what MMPB/GBSA method is most used for...

And in the command line it was recommended to use reference .pdb structure . I am not using them. Using them can help me to get a better results ? 

Your system runs fine as is, no need to include a reference structure

And it was also mentioned that Hydrogen should not be present .two complex files that have I sent few days ago will they be okay to work with in this regard ?

Whether the quality of your predicted complex is good or not I can't say, it is up to you to deem what is best taking into consideration your knowledge of the system and the experimental results

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