where r is the Cartesian coordinate of the atom specified in the subscript, and | • • • | symbolizes the Euclidean distance. The free energy profiles are shown in figure , in which DFTB3-3OB is represented in blue, whereas DFTB2-MIO/halorg is pictured in black. In figure , two sets of results are shown for each DFTB method, in which different van der Waals (vdW) parameters are used. Indeed, we observed that the reaction free energy largely depends on the vdW parameters, which has a large impact on the water solvation sphere formed around the leaving anion. In the first set of simulations, we adopted the vdW from the Amber99sb forcefield besides those of fluorine, which we took from the GAFF forcefield. As it can be observed, in both cases (DFTB2/MM and DFTB3/MM) the reaction is largely endothermic, contrary to ab initio simulations. In particular, the reaction free energy is 9.59 ± 0.01 kcal•mol -1 and 7.36 ± 0.01 kcal•mol -1 for DFTB3-3OB/MM and DFTB2-MIO/MM, respectively. In a second set of calculations, we use the vdW parameters of chloride and fluoride provided by Joung and Cheatman, specifically optimized for the TIP3P water model (the specific values are available in the supporting information). Using such parameters, the results are in better accordance with ab initio results. The reaction free energy with DFTB3-3OB/MM is still endothermic (1.23 ± 0.01 kcal•mol -1 ), confirming what was observed in previous reactions that DFTB3 tends to favor endothermic reactions. In contrast, DFTB2/MM predicts a weakly exothermic reaction (-0.89 ± 0.01 kcal•mol -1 ) in qualitative agreement with results reported in the literature. As for the activation barrier, the values are quantitatively closer to experiment by using the GAFF vdW parameters: 20.15 ± 0.01 kcal•mol -1 for DFTB3-3OB and 18.59 ± 0.01 kcal •mol -1 for DFTB2-MIO, while using the optimized vdW parameters we found values of 15.75 ± 0.01 kcal•mol -1 and 13.70 ± 0.01 kcal•mol -1 for DFTB3-3OB and DFTB2-MIO, respectively. In both cases, DFTB3 is closer to the experimental value, but it fails to reproduce the products as more stable than the reactants. A similar tendency was observed for this method of DFTB in the proline case study. Another interesting point of comparison is the value of the collective variable at which the free energy transition state is located since it also changes with the vdW parameters and DFTB method used, as evidenced in figure . Using the GAFF vdW parameters the maximum was found at a value of 0.53 for DFTB2-MIO and 0.76 for DFTB3-3OB, whereas using the optimized vdW parameters the transition state is found at 0.57 and 0.38 for DFTB3 and DFTB2 respectively.