MD simulations were carried out by using the Desmond engine with the OPLS4 force field. The system encompassed the protein-ligand/cofactor complex, a predefined water model (TIP3P) as a solvent, and counterions (Na + or Cl -adjusted to neutralize the overall system charge). The system was treated in a cubic box with a periodic boundary condition (PBC) specifying the shape and size of the box as 13 Å distance from the box edges to any atom of the protein. Short-range coulombic interactions were calculated using 1 fs time steps and 9.0 Å cutoff value, whereas long-range coulombic interactions were estimated using the Smooth Particle Mesh Ewald (PME) method. Each system generated from CatL and the ligand was subjected to at least 5 μs simulations (five replicas of 1 μs each) with random seeds. Atomic interactions and distances were determined using the Simulation Event Analysis pipeline as implemented in Maestro 2021.4 (Schrödinger LCC) using standard options. Representative frames of the simulations were retrieved using hierarchical clustering analyses. Trajectories were clustered using the script trj_cluster.py (implemented in Maestro 2021.4, Schrödinger LCC) according to the root-meansquare deviation (RMSD) of ligand's heavy atoms, using 1 Å as a cut-off (see Figure ). RMSD values of the protein backbone were used to monitor simulation equilibration and protein folding changes (see Figure ) All the trajectory and interaction data are available on the Zenodo repository (code: 10.5281/zenodo.6984711). MD trajectories were visualized, and figures produced by PyMOL v.2.5.2 (Schrödinger LCC, New York, NY, USA). the project. P.F., J.B., M.G., and T.P. wrote the manuscript with contributions from all coauthors. All authors have given approval to the final version of the manuscript.