This finding emphasizes the importance of carefully considering atom mappings, especially for ligand pairs in complex environments. Ensuring that the input coordinates accurately represent the desired binding mode in a 3D coordinate system is crucial to avoid potential issues during simulations. These results indicate that the rotation around Tors 4-5 and Tors 5-6 can occur in the water environment, but not in the complex. Combined with our findings in the 8, this indicates the possibility for these re-alignments to lead to sampling issues should they not be resolved during system equilibration.