Hi,
I'm trying to run a molecular dynamics on a drug-enzyme complex. I did John Kerrigan's tutorial and everything worked fine. Now I'm trying with my system but I get a problem : the ligand keeps falling out of the active site during EM. I thought maybe it was a pbc problem and used comm-grps = protein in my .mdp file, but I get the same result. I transformed the .gro input file to .pdb to view it in pymol and the ligand is in the active site before simulation. So it seems this happens during steepest descents EM.
This means that it is lower energy for the ligand not to be in the binding site (at least, in its starting configuration) for some reason, assuming you have everything set up properly.
Is there a way to keep/force the ligand in the active site during EM (maybe using PR) ?
You could restrain it to stay in the binding site using distance restraints or position restraints or some such. But this may only mask some larger problem.
Is this reflecting some physical phenomenon, ie the ligand has low affinity ?
Hard to say. Where are you getting your starting coordinates? I doubt it is reflecting low affinity, as in my experience even low affinity ligands will stably stay in binding sites for relatively long times in MD, and definitely during energy minimization. It more likely means that your starting structure is not very good -- i.e. the ligand is sterically clashing with something in the binding site such that energy minimization moves the ligand to lower energy by removing the steric clashes and partly pushing the ligand out of the binding site. There are of course other possibilities... Your ligand parameters could be bad, etc. You could certainly solve the problem of it leaving during energy minimization by restraining it to stay in the binding site, but then it will probably just leave during MD, so I think you'd probably just be masking the problem. I would look carefully at your starting structure and doublecheck your parameters and so on. David
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