[gmx-users] ligand falling out of active site during EM

[David Mobley]

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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