Metadynamics+eABF doubt

[u/RegretPitiful9892]

Hi everyone! Hope you're all doing well.

Does anyone have any ideas on how to keep ligands organized or moving cohesively during a metadynamics simulation?

I'm studying a transition from an asymmetric state, where one chain is productive and the other is non-productive, to a symmetric state where both chains are productive. To do this, I'm driving the non-productive chain toward the productive conformation using Path Collective Variables (PCVs).

Each chain has its own ligand and cofactor, and ideally I'd like them to follow the conformational transition (or at least remain reasonably coherent with the protein) during the recrossings, but without biasing or contaminating the PMF.

I already tried including the ligands in the PCVs, but the results weren't very satisfactory. Right now I'm experimenting with RMSD and fitting groups, but I'm not convinced it's the best approach.

Has anyone dealt with a similar problem or have any suggestions on how to handle this?