proves on the shortcomings of the restraint method In Fig. (b), the RMSD is mostly stable with an average of (0.26 ± 0.06) Å. There are a few larger fluctuations around 10 ns and 40 ns. These fluctuations can be explained by a movement of the Tyr67 residue (see Fig. ). At the start of the simulation, the face of the Tyr67 interacts with the face of the benzene ring of the ligand (see Fig. ). However, at around 10 ns, Tyr67 swings away from the ligand, which allows the R 1 bromine to take up this space, causing the ligand to swing towards Tyr67. Similarly, at around 37 ns, Tyr67 moves further away from the ligand, which then moves slightly closer to Tyr67, potentially to keep the π-π interactions. Pemberton et al. 1 also list Tyr67 as a key residue for ligand 16 binding to VIM-2. Furthermore, the R 3 -His263 σ-π stacking interaction present in the QM/MM and also mentioned by Pemberton et al., is not present in the MD simulation.