As mentioned above, the main energy difference between the modified DFTB3 Hamiltonian and the DFT reference is observed for the formed enolate after passing the transition state. It is possible that the nature of the DFTB3 Hamiltonian is not able to describe the NADP + and enolate correctly, as they involve considerably charge separation. This has been reported to be a challenge for DFTB3 due to the use of a minimal basis sets, which significantly underestimates polarizability. Modifications to include a larger basis set are beyond the scope of this work. However, this error can be easily corrected by adding a correction accounting for the difference in the electronic energy at higher DFT level.