Hamiltonian. As reference, we carried out QM/MM molecular dynamics simulations with the adaptive string method at the M06-2X/def2-SVP/CHARMM36 level of theory. Figure depicts the comparison between both free energy profiles (black and blue curves), as well as the corrected one by means of single point calculations at the M06-2X/def2-TZVP/CHARMM36 level of theory (curve in red). The new DFTB3 Hamiltonian (curve in blue) reproduces the reference activation barrier (curve in black) within 0.1 kcal/mol, anticipating the transition state along the reaction path. This result is validated by the DFT-based corrections on the optimized DFTB3 profile, with a barrier of only 1.5 kcal/mol higher (see Figure ), while at the enolate region the energies were up to 8.8 kcal/mol higher. Here, it is worth to mention that these deviations are similar to the ones in the QM/MM potential energy profiles (see Figure ). On the other hand, the corrected profile in red showed good agreement with the profile obtained at the M06-2X/def2-SVP/CHARMM36 level of theory. The disagreements in these results could be explained by slight differences in geometries. As shown in Figure , although the geometries at the transition state were improved by the modifications made to the original DFTB3's RPFs (see the green curve in Figure ), they still reproduce slightly shorter donor-acceptor C-C distances (CV3, Figure ) compared to reference M06-2X/def2-SVP geometries.