I have docked the substrate in the active site of the protein ( contains NAD and lactate substrate ), interacting with binding residues through hydrogen bonding. When i start the MD simulation using Gromacs, After few ns the lactate substrate moves toward outside of the binding pocket. How to solve this issue ?
Hi Abdul,
The predicted ligand pose may not be stable in the active site, hence it is moving out.
There are cases, where the ligand molecules move from the cavity will be back to its original position when you extend the simulation.
My suggestion is instead of using the lowest energy complex, select the top 5 complexes and run a few ns simulation that will give an idea about complex stability.
One should not run the production simulation with constraints, unless a specific reason. There is two type of inhibition mechanism exists one is reversible and irreverrsible. If you are able to see the ligand moving away from the complex it may be reversible inhibitor (A good literature survery may help to understand the problem). On other hand, it may be due to the technical problems occured during the preparation or the molecule may not be a good inhibitor or you may need to try in different active sites.
Mr Mohsin Yousuf Lone i have run it for 20ns, but its move out after 3 ns.
Nikhil Maroli , i have docked the substrate which has weak interaction as compared to when we have inhibitor in the active site.
I came to know that when i am running the NPT and NVT file, the ligand is moved from the native position which looks i didn't put the constrain in the right way or there is some issue with NPT or NVT file while using gromacs
Then, maybe you can try another pose. Or, if you are confident about the current one, then you may launch a few more simulation runs with it. The ligand could stay longer in some of them.
You can change the force field and see if the same results are obtained.
Anu Manhas Mam, I agree. Change the force field and then check if you get the same results or not.
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