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Molecular Dynamics Simulation of Protein-Ligand using Gromacs
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- Опубликовано: 26 июл 2022
- This tutorial will guide a new user through the process of setting up a simulation system containing a protein Mpro-SARS-CoV-2 in complex with a ligand (Nirmatrelvir). This tutorial focuses specifically on issues related to dealing with the ligand, assuming that the user is familiar with basic GROMACS operations and the contents of a topology.
#Ligand: pubchem.ncbi.nlm.nih.gov/comp...
CHARMM Topology: mackerell.umaryland.edu/charmm...
#Latest #charmm36-jul2021.ff forcefield: mackerell.umaryland.edu/downlo...
#CGenff Server: cgenff.umaryland.edu/initguess/
#CHARMM to GROMACS format: mackerell.umaryland.edu/downlo...
#sort_mol2_bonds.pl: www.mdtutorials.com/gmx/comple...
MDP files:
ions.mdp: www.mdtutorials.com/gmx/comple...
minim.mdp: www.mdtutorials.com/gmx/comple...
nvt.mdp: www.mdtutorials.com/gmx/comple...
npt.mdp:www.mdtutorials.com/gmx/comple...
md.mdp:www.mdtutorials.com/gmx/comple...
Github link:
github.com/pritampanda15/Mole...
Notes:
The ion names have been updated to SOD for NA and CLA for CL.
gmx genion -s ions.tpr -o solv_ions.gro -p topol.top -pname SOD -nname CLA -neutral
For updated coordinate numbers in topol.top: highest number - lowest number / 3
Music
Almost in F - Tranquillity by Kevin MacLeod is licensed under a Creative Commons Attribution 4.0 license. creativecommons.org/licenses/...
Source: incompetech.com/music/royalty-...
Artist: incompetech.com/
#gromacs
#mdsimulation
#protein-ligand
#ligand
#charmm
#topology
#bioinformatics
#biophysics
Thank you so much sir, i got my error solved related to water and ions molecule type
Excellent
Sir, please make a video on enhanced sampling methods like umbrella sampling, accelerated molecular dynamics simulations for free energy landscapes calculations.
Will try to definitely 👍
sir i am jibin, research scho. beautiful explanation, in between errors are good for more understanding, kindly upload a tutorial based on NAMD, Thank you so much
Thank you very much
at early stage of the tutorial but why do we need to separate the ligand from the complex if we need to creat back the complex out of the separated ligand and the receptor? why don't we directly use the complex from vina result? can you make a video on the result analysis please, Sir?
That’s because you need to parameterize the ligand and protein separately. Topology of ligand and proteins differ.
@@BioinfoCopilot appreciate for your reply. Thank you! I have tried many tutorials on docking and MD simulations, but, as a new to the discipline, I found your tutors are really very helpful to get into it. would be grateful, as you did in the docking tutorials, if you can make a video on the MD result analysis, not sure if you make before.
Thank you very much! Yes will try my best to make a video on that. Thanks much
nice tutorial. thank you sir
You are 🙏 welcome
Thank you for great tutorial. I got WARNING message for gmx grompp npt.mdp (skiped in your video). The WARINIG 1 is "The Berendsen barostat does not generate any strictly correct ensemble, and should not be used for new production simulations (in our opinion). For isotropic scaling we would recommend the C-rescale barostat that also ensures fast relaxation without oscillations, and for anisotropic scaling you likely want to use the Parrinello-Rahman barostat.". How do I solve thie warning? The process is finished with -maxwarn 1, but I wonder that what is fundamental problem in nvt.mdp for my complex data.
Like the error message you have received, you just have to modify the gromacs nvt parameters to see the results and compare with previous one. Since your system is a complex one I would recommend you to use CHARMM-GUI for the same.
hi sir .
How does one extend the protein simulation in Gromacs ?
for exemple 50ns finished and i want to extend it to another 50ns ? thanks in advance.
gmx_mpi convert-tpr -s md_0_1.tpr -extend 100000 -o next.tpr
gmx_mpi mdrun -s next.tpr -deffnm md_0_1 -cpi md_0_1_prev.cpt
What's the reason behind using SPCE water model instead of the CHARMM recommended TIP3P model?
Yes, you are right. I have used it just for the sake of tutorial. You have to optimize based on your needs. Of course TIP3 goes will with CHARMM. With the 104 deg H-O-H angle TIP3P has slightly better structural and thermodynamic properties than SPC or SPC/E models (which have their own flaws). Another reason is that all of the CHARMM protein, nucleic acid, lipid, carbohydrate, etc., parameters have been developed wrt. to the TIP3P water model. The most promising (but costly) development is the TIP4Pew water model; diffusion is much improved, and the model is close enough to TIP3P that it should be a reasonable change for use with CHARMM macromolecule parameters.
Thank you very much !
Welcome
Dear sir...plz make tutorials on MMPBSA/ MMGBSA calculation based on gromacs protein-ligand md result
Sure will do that
While generating unk.str (14:27) file for my ligand of interest I am getting gap penalty that is more than 50 . What can I do about that ?
Could you share the log files
Hi, if you can help me please
When i run the command to calculate the H-bonds ''gmx hbond -s md.tpr -f md_center.xtc -num hb.xvg'' I can't find anything ( the file hb.xvg does not contain the number of H-bonds).
I also tchecked the ''complex.gro'' and i analyzed the RMSD, RMSF, Rg successfully.
I use Gromacs 2023.
It should generate the xvg file. Check properly. gmx hbond -f md.xtc -s md.tpr -n index.ndx -num hbnum.xvg. www.compchems.com/how-to-study-hydrogen-bonds-using-gromacs/#how-to-compute-the-hydrogen-bonds-between-two-groups
Sir, can I study the nature of interaction between the two dimensional material and methane molecule in gromacs? Can you suggest how to insert such a kind of system in the Gromacs?
Yes you can. You can refer to CHARMM-GUI to setup the parameters
Thank you for the amazing tutorial. Why did you divide by 3 (at 50:49) to solve error of the difference of the coordinates in topol.top and solv_ions.gro file ?
Thank you very much! I divided by 3 since we are going to add or subtract water molecules. H2O consists of 3 atoms so thats why I divide it by 3. The formula is highest number of atoms (coordinates) - lowest no. of atoms / 3
@@BioinfoCopilot Thank you so much for clearing my doubt.
But it is only useful upto python version 3.7.3
Newest version is 3.10
Not working
Great tutorial sir.
I got some error like
The residues in the chain GLN127--PRO390 do not have a consistent type. The
first residue has type 'Protein', while residue TPO287 is of type 'Other'.
Either there is a mistake in your chain, or it includes nonstandard residue
names that have not yet been added to the residuetypes.dat file in the GROMACS
library directory. If there are other molecules such as ligands, they should
not have the same chain ID as the adjacent protein chain since it's a separate
molecule.
Can you please help to resolve this?
Use Swiss PDB viewer to fix the missing chains. Remove water molecules and ligands/small molecules etc. use the clean protein only then process it with pdb2gmx.
Thank you very much for your time and effort.👋👋
In the step of preparing the topology of the Ligand, in particular during the generation of the .str file (stream" file).
I tried with a complex based on Iron II (organo-mitalic compound) but an error that blocks me, because element (iron) not supported.
Please, Could you suggest me another method or another WEB server.
Thank you 🙏. Since you are dealing with metals then you should try CHARMMGUI.
@@BioinfoCopilot thank you very much, i will try
@@BioinfoCopilot
First thank you very much,
As you recommended me, I tried with CHARMM-GUI
by option: Ligand Reader & Modeler
but it does not work with complex (organo-metallic).
Have you tried using nanomaterials modeller. If that also doesn’t work then use LAMMPS. It has all the potentials for metal ions.
@@BioinfoCopilot Thank you very much, I will try.
Whenever I minimise my protein I get the following error “floating point exception (core dumped)” any advice please? I need this calculations asap
Its the problem with your protein preparation. Use CHARMM-GUI for the protein simulation.
Thank you for this great tutorial. My protein-ligand complex has two conserved water molecules and I want to retain them during simulation. Could you please tell how can I do it?
My pleasure. Firstly name the water molecules to WAT inside the protein ligand complex. Then add explicit solvent model as described by GROMACS. In this way you can identify your water molecules inside the complex otherwise everything will be named as SOL.
@@BioinfoCopilot Thank you. I will try it.
Can you do the MD Simulation for 2 ligands with one protein. You will be compensate for the same.
Thanks for the offer. However, I am here for teaching or for making tutorials only.
HI sir, If I runnig a complex simulation, Can I go to my other work with the system at the same time?
Yes definitely
Thank you for the helpful tutorial, why for install " pip install networkx==2.3" this error will appear for me " Could not find a version that satisfies the requirement networkx==2.3 (from versions: 0.34, 0.35, 0.35.1, 0.36, 0.37, 0.99, 1.0rc1, 1.0, 1.0.1, 1.1, 1.2rc1, 1.2, 1.3rc1, 1.3, 1.4rc1, 1.4, 1.5rc1, 1.5, 1.6rc1, 1.6, 1.7rc1, 1.7, 1.8rc1, 1.8, 1.8.1, 1.9rc1, 1.9, 1.9.1, 1.10rc2, 1.10, 1.11rc1, 1.11rc2, 1.11, 2.0, 2.1, 2.2rc1, 2.2)
No matching distribution found for networkx==2.3"
Thank you! Have you performed the operation in anaconda environment. If not then please do it in conda environment. Or else do the following: pip uninstall networkx and then apply your command.
Also this version of networkx only works for python 3 distribution.
Is there any particular reason for choosing spce water model instead of CHARMM recommended tip3p water model ?
Yes, you are right. I have used it just for the sake of tutorial. You have to optimize based on your needs. Of course TIP3 goes will with CHARMM. With the 104 deg H-O-H angle TIP3P has slightly better structural and thermodynamic properties than SPC or SPC/E models (which have their own flaws). Another reason is that all of the CHARMM protein, nucleic acid, lipid, carbohydrate, etc., parameters have been developed wrt. to the TIP3P water model. The most promising (but costly) development is the TIP4Pew water model; diffusion is much improved, and the model is close enough to TIP3P that it should be a reasonable change for use with CHARMM macromolecule parameters.
Hi thanks for the awesome tutorial. I hv two main questions please! (1) My ligand’s name is not UNL or LIG or something, in my complex, the ligand is represented witg a star (*) sign so grep doesn’t work. So can I change the name manually in some text editor ? (2) the python script gives me the error: invalid syntax I hv double checked and I don’t think there is any issue with the command then I don’t know why? Any suggestions please. Thank you
Use Discovery Studio for renaming the complex file. Also update the same for .str file as well. I think there is a mismatch between the .str file and your ligand molecule. Fix that and I think it will definitely work. One more thing open the complex file in text editor and change the name to UNK or LIG. Yes you can do that.
@@BioinfoCopilot thank you sir 🤗
sir, I appreciate making this great tutorial video, I have a question about protein-ligand MD calculation on Gromacs, after I run protein-ligand python3 cgenff_charmm2gmx_py3_nx2.py UNL ligand_fixed.mol2 UNL.str charmm36-jul2021.ff, it show error as follows: File "/usr/local/lib/python3.10/dist-packages/numpy/__init__.py", line 313, in __getattr__
raise AttributeError(__former_attrs__[attr])
AttributeError: module 'numpy' has no attribute 'int'.
`np.int` was a deprecated alias for the builtin `int`. To avoid this error in existing code, use `int` by itself. Doing this will not modify any behavior and is safe. When replacing `np.int`, you may wish to use e.g. `np.int64` or `np.int32` to specify the precision. If you wish to review your current use, check the release note link for additional information.
The aliases was originally deprecated in NumPy 1.20; for more details and guidance see the original release note at:
numpy.org/devdocs/release/1.20.0-notes.html#deprecations. Did you mean: 'inf'?
To resolve the error in your code, I replace instances of np.int with int. Here's how I wrote the code: import numpy as np
def SECOND_ORDER_LOG(self, img):
original = np.zeros((5, 5), dtype=int), and I also pip upgrade numpy.
However, it still show same error, I do not know whether python3 cgenff_charmm2gmx_py3_nx2.py is not compatible python3.10.6 -my python version and any other issues, if you have any suggestion, I sincerely appreciate it. Thanks
Clearly its numpy error. Check stackoverflow to troubleshoot it
create an environment (networkx) at conda and there installed Python3.7.3 and networkx=2.3, then run the python script. IT WORKED FOR ME
Hello sir, Its been two days I haven't got activation mail from Cgenff. is there any alternative to generate topology for ligand
It takes time. So please have patience. Use your academic email address.
Thank you sir for this great tutorial.Is it necessary to add comm-grps for protein-liangd group?
Thank you 🙏. Yes it is necessary
Hello sir. Your tutorial very helpfull for me to doing my undergraduate thesis. I have question, How long time for md production running? i was run production md 5000000 steps, 10000.0 ps.
and takes time more than 2 days until now haven't done. I running on pc 4 ram and 8 vcpus. I running for 77 atoms. It is normal or something problem with my job? Thanks
Thank you very much! Yes it is normal to take couple of days to complete 10ns. You are using your laptop with minimal configuration. That’s why it is taking long time. Bur my question is what is your model that only contains 77 atoms? Let me know so that you can optimize your script.
Sir i am not able to import networkx as nx any help
You have to use a specific version of network x. Not all versions will work.
where can i download the updated forcefield sir?
www.charmm.org/archive/charmm/resources/charmm-force-fields/
www.charmm.org/archive/charmm/resources/charmm-force-fields/download.php?filename=CHARMM_ff_params_files/archive/charmm36-mar2019.ff.tgz
@@BioinfoCopilot Thank you for sharing the link sir. But the site is not reached...I couldn't able to download the Forcefields .
It’s working for me.