Pitambar,
your guess about a ligand parameterization issue seems reasonable to me,
if you start from a known complex structure.
I'd suggest to check the ligand parameters, i.e. atom types and charges,
as well as the structural elements (planarity vs. non-planarity) of the
ligand (=> minimization/simulation of the free ligand).
Additionally, ensure that the ligand has the correct molecular charge
and protonation state when simulating the bound state.
Maybe key polar interactions between ligand and protein are not
correctly modelled and you want to try a different charge generation method.
If you do not start from a known complex structure, then the protein
environment of the binding pocket might disfavor ligand binding: your
protein could have different conformations in bound and unbound state.
Maybe that helps.
Best,
Anselm
Bioinformatik | NHR.FAU
Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Germany
Am 19.06.2025 um 22:57 schrieb Pitambar Poudel via AMBER:
> Hello all,
> I’m working on a system consisting of a transporter protein with a ligand
> positioned at a binding pocket and the whole system embedded in a lipid
> bilayer. The bilipid layer was constructed using packmol-memgen. Before
> that, I used Antechamber for ligand parameterization with the following
> script:
>
>
> *antechamber -i ligand.mol2 -fi mol2 -o UNL.mol2 -fo mol2 -c abcg2 -s 2 -pf
> y -j 5 -at gaff2 -nc 0 antechamber -i UNL.mol2 -fi mol2 -o UNL.prep -fo
> prepi -c abcg2 -s 2 -pf y -j 5 -at gaff2 -nc 0 parmchk2 -i UNL.prep -f
> prepi -o UNL.frcmod -s 2*
> During equilibration, with gradually decreasing positional restraints (~100
> ns), the system remains stable. However, once restraints are fully lifted
> in the production run, the ligand instantly dissociates and flies away.
> Initially, I had used -j 4, but some double bonds were incorrectly assigned
> during parametrization, so I switched to -j 5 as it allows to read the
> connectivity table from the input and then run ’bondtype’ and ’atomtype’
> sequentially. My current guess is that the issue lies in ligand
> parametrization—possibly incorrect charges or missing parameters. I don't
> see issues after running parmchk2, however. Any suggestions or insights
> would be appreciated.
> *Pitambar Poudel*
> Graduate Research Assistant
> Computational Biophysics and Bioinformatics Lab
> Department of Physics and Astronomy, Clemson University
> *Lab: http:/compbio.clemson.edu/ <http://compbio.clemson.edu/lab/>*
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Received on Fri Jun 20 2025 - 03:00:02 PDT
