All simulations were run using the SHAKE algorithm for keeping the bonds involving hydrogen still, with the exception of the full MM phenol simulations. In all the cases, the heating and equilibration protocols were performed treating the whole system at the MM level. Production runs were performed in the NVT ensemble using the Langevin thermostat, with a collision frequency of 5 ps -1 . The ML/MM production runs were performed starting from the last frame of the equilibration protocol. In the case of phenol, the time step was 0.5 fs and the system was also simulated in vacuo, for further comparison. The ML/MM simulations of the oxazole-4-carbaldehyde, the alanine dipeptide and the protein complexes used a time step of 1 fs, and the corresponding MM simulations a time step of 2 fs. In every case in which QM/MM simulations were performed for comparison, the time step was the same as in the ML/MM case.