gmx_MMPBSA Index Error

[Nishant Raj]

Hi,

I wanted to calculate thermodynamic parameters such as free energy of binding for the ligand using MM-PBSA. But facing some error while running the gmx_MMPBSA, am pasting the commands along with the error message. help me to fix this issue.

COMMAND USED:

gmx_MMPBSA -O -i mmpbsa.in -cs md_0_nico_50.tpr -ci index.ndx -cg 1 13 -ct md_0_nico_50_fit.xtc -cp topol.top

ERROR:

[INFO   ] Starting gmx_MMPBSA v1.6.0
[INFO   ] Command-line
  gmx_MMPBSA -O -i mmpbsa.in -cs md_0_nico_50.tpr -ci index.ndx -cg 1 13 -ct md_0_nico_50_fit.xtc -cp topol.top

[INFO   ] Checking mmpbsa.in input file...
[INFO   ] Checking mmpbsa.in input file...Done.

[INFO   ] Checking external programs...
[INFO   ] cpptraj found! Using /userdata/ibsd/tools/miniconda3/envs/gmxMMPBSA2/bin/cpptraj
[INFO   ] tleap found! Using /userdata/ibsd/tools/miniconda3/envs/gmxMMPBSA2/bin/tleap
[INFO   ] parmchk2 found! Using /userdata/ibsd/tools/miniconda3/envs/gmxMMPBSA2/bin/parmchk2
[INFO   ] sander found! Using /userdata/ibsd/tools/miniconda3/envs/gmxMMPBSA2/bin/sander
[INFO   ] Using GROMACS version > 5.x.x!
[INFO   ] gmx found! Using /userdata/ibsd/tools/miniconda3/envs/gmxMMPBSA2/bin.AVX2_256/gmx
[INFO   ] Checking external programs...Done.

[INFO   ] Building AMBER topologies from GROMACS files...
[INFO   ] Get PDB files from GROMACS structures files...
[INFO   ] Making gmx_MMPBSA index for complex...
[INFO   ] Normal Complex: Saving group Protein_nico (1_13) in _GMXMMPBSA_COM_index.ndx file as _GMXMMPBSA_COM.pdb
[INFO   ] No receptor structure file was defined. Using ST approach...
[INFO   ] Using receptor structure from complex to generate AMBER topology
[INFO   ] Normal Receptor: Saving group Protein (1) in _GMXMMPBSA_COM_index.ndx file as _GMXMMPBSA_REC.pdb
[INFO   ] No ligand structure file was defined. Using ST approach...
[INFO   ] Using ligand structure from complex to generate AMBER topology
[INFO   ] Normal Ligand: Saving group nico (13) in _GMXMMPBSA_COM_index.ndx file as _GMXMMPBSA_LIG.pdb
[INFO   ] Checking the structures consistency...
[INFO   ]
[INFO   ] Using topology conversion. Setting radiopt = 0...
[INFO   ] Building Normal Complex Amber topology...
/userdata/ibsd/tools/miniconda3/envs/gmxMMPBSA2/lib/python3.9/site-packages/parmed/gromacs/gromacstop.py:1035: GromacsWarning: The [ pairs ] section contains 12 exceptions that aren't 1-4 pairs; make sure you know what you're doing!
  warnings.warn('The [ pairs ] section contains %i exceptions that '
[INFO   ] Detected CHARMM force field topology format...
[INFO   ] Assigning PBRadii mbondi2 to Complex...
  File "/userdata/ibsd/tools/miniconda3/envs/gmxMMPBSA2/bin/gmx_MMPBSA", line 8, in <module>
    sys.exit(gmxmmpbsa())
  File "/userdata/ibsd/tools/miniconda3/envs/gmxMMPBSA2/lib/python3.9/site-packages/GMXMMPBSA/app.py", line 98, in gmxmmpbsa
    app.make_prmtops()
  File "/userdata/ibsd/tools/miniconda3/envs/gmxMMPBSA2/lib/python3.9/site-packages/GMXMMPBSA/main.py", line 689, in make_prmtops
    self.FILES.mutant_receptor_prmtop, self.FILES.mutant_ligand_prmtop) = maketop.buildTopology()
  File "/userdata/ibsd/tools/miniconda3/envs/gmxMMPBSA2/lib/python3.9/site-packages/GMXMMPBSA/make_top.py", line 125, in buildTopology
    tops = self.gmxtop2prmtop()
  File "/userdata/ibsd/tools/miniconda3/envs/gmxMMPBSA2/lib/python3.9/site-packages/GMXMMPBSA/make_top.py", line 569, in gmxtop2prmtop
    action = ChRad(com_amb_prm, PBRadii[self.INPUT['general']['PBRadii']])
  File "/userdata/ibsd/tools/miniconda3/envs/gmxMMPBSA2/lib/python3.9/site-packages/parmed/tools/changeradii.py", line 1026, in ChRad
    _call_method[radii_set](parm)
  File "/userdata/ibsd/tools/miniconda3/envs/gmxMMPBSA2/lib/python3.9/site-packages/parmed/tools/changeradii.py", line 289, in mbondi2
    if atom.bond_partners[0].atomic_number == 7:
IndexError: list index out of range
Exiting. All files have been retained.

[marioe911116]

it seems your ligand contains LPH particles... if so please check this tutorial in the docs

https://valdes-tresanco-ms.github.io/gmx_MMPBSA/dev/examples/Protein_ligand_LPH_atoms_CHARMMff/

[Mario Ernesto]

can you send the files to check?

El mar, 28 mar 2023 a las 23:24, Nishant Raj (<nisn...@gmail.com>) escribió:

After following the suggested tutorial, got another MMPBSA error.

Please check the error screenshot attached with this mail.

And help me to resolve the problem.

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[Nishant Raj]

Please check the attached files:

 traj_0.pdb

 traj_10.pdb

 traj_11.pdb

 traj_12.pdb

 traj_20.pdb

 traj_50.pdb

On Sat, Apr 1, 2023 at 4:47 AM Mario Ernesto <marioe...@gmail.com> wrote:

could you please send me a couple of frames of the trajectory without any transformation?

El vie, 31 mar 2023 a las 5:57, Nishant Raj (<nisn...@gmail.com>) escribió:

Sure, I will do that. 

I'm attaching the associated tpr and itp files.

On Fri, Mar 31, 2023 at 11:26 AM Mario Ernesto <marioe...@gmail.com> wrote:

Please, let's keep the conversation in the google group as it's better for me to keep tracking... I see your str_noLP.pdb structure doesn't contain the structure at all... please, send me the tpr file you are using and all the itp associated with the topology

El jue, 30 mar 2023 a las 23:33, Nishant Raj (<nisn...@gmail.com>) escribió:

I am attaching all the related files here, which I generated by following the above  mentioned tutorial. Please check the files attached with this email.

[Nishant Raj]

After following the suggested tutorial, got another MMPBSA error.

Please check the error screenshot attached with this mail.

And help me to resolve the problem.

On Mon, 27 Mar, 2023, 9:23 pm marioe911116, <marioe...@gmail.com> wrote:

[marioe911116]

can you share the folder where you have all the files you are using? that way is going to be easier to help you

[Nishant Raj]

  I'm sharing the folder link which i uploaded to my drive. The folder contains files upto md production without recentering and translational fitting. Also the "nvt.xtc" and "npt.xtc" were not included in the folder because of their large sizes. If it required then i will share them individually, please let me know.

Thanking you in advance.

https://drive.google.com/drive/folders/1m95yu54bZMt8-pwpsFBiXeiuHzg68oKK?usp=sharing

 nicolsamide_all_files

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[Nishant Raj]

Actually I'm working through remote login in a HPCC system. So, it's difficult to share the whole folder, but I'm trying.

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[marioe911116]

got a quick question... Is the ligand not bound to the protein? I assume complex.gro file is the file that is generated when the protein and the ligand files are concatenated and doesn't have any PBC or stuff like that. When I open this file in a visualizer, I see the ligand is not near the protein. Cna you comment on that?

[Nishant Raj]

Yes, ligands are not bound to the protein. actually we just followed the gromacs " protein-ligand complex" tutorial and we are new to the md simulation. We have 9 ligands with the same protein including the niclosamide and followed the same pipeline for all the ligands. Now  we checked "complex.gro" and "solv.gro" of other  ligands and some of them were the same as niclosamide(ligands not bounded with protein), but the gmx_mmpbsa of those ligands worked properly. please suggest what should we do in this case.

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[marioe911116]

well, is the ligand is not bound to the protein, there is nothing gmx_MMPBSA can do... you will need to redo those simulations with the proper binding pose

[Nishant Raj]

 How can i bind the ligand with protein? I created the complex using a text editor, what else i can do to bind them? Also from another ligand-protein complex (without  proper bounding of protein and ligand) i got the result  i'm attaching the result file here , without the proper binding what this file means ?

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[marioe911116]

the issue as you can see in the result files is not the calculation, is that the ligand is not bound to the protein and that's why the binding free energy is almost zero... please, review carefully the initial structures you are using to run the MD simulations as it is obvious something is going wrong during the assembly process. If you are performing docking before runing the MD simulations, my advice is to use the protein strcture file that you used for docking with the same coordinates as starting structure for the MD and then do the assembly with the ligand pose that should also come from docking.  

[Nishant Raj]

We tried with the docked protein and ligand, but it's also not binding. We are also trying with other ways, but not sure for the result. Could you provide us some suggestions, to bind the protein and ligand? 

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[Mario Ernesto]

how is the ligand not bound after the docking process? something is going wrong with the assembly of the receptor and the ligand because, after the docking process, you should get different poses for the ligand in the active site... have you checked AMDock (https://github.com/Valdes-Tresanco-MS/AMDock-win/wiki)? It will ease the docking and the assembly process for you 

[Mario Ernesto]

OK, that looks better... regarding CGenFF, I don't use it personally, so I don't know about those issues

El jue, 6 abr 2023 a las 1:32, Nishant Raj (<nisn...@gmail.com>) escribió:

Hi,

I tried with another ligand (zingerol), the protein and ligand got bounded. Could you please check these files whether these are correct or not? 

I have a total of 9 ligands, i generated the ligand parameter files(ligand.str) using CGenFF server for 7 ligands but the server is not working for 2 ligands. Do you have any idea of how to fix those errors(error in carbonyl group, resonance structure) or do you know any alternatives for ligand parameter generation from CHARMM force field. I tried with CHARMM-GUI but it is also not working.

Thank you

[Nishant Raj]

Hi,

I tried with another ligand (zingerol), the protein and ligand got bounded. Could you please check these files whether these are correct or not? (I am attaching the drive folder link).

I have a total of 9 ligands, i generated the ligand parameter files(ligand.str) using CGenFF server for 7 ligands but the server is not working for 2 ligands. Do you have any idea of how to fix those errors(error in carbonyl group, resonance structure) or do you know any alternatives for ligand parameter generation from CHARMM force field. I tried with CHARMM-GUI but it is also not working.

 Thank you

 simulation_&_mmpbsa_result

[Shiv Bharadwaj]

Hello!

Use the following server: 

https://www.swissparam.ch/

or https://bmcresnotes.biomedcentral.com/articles/10.1186/1756-0500-5-367, on your system or server. 

Hope it's helpful

Best

SvB

P.S. Prepare your ligand in Chimera by removing H-atoms first and adding H-atoms and charge under default parameters.

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