These calculations served as a reference for the accuracy and reliability of our modified DFTB3 RPs. Additionally, we applied the modified RPs to the well-known Dihydrofolate Reductase (DHFR) enzyme where they significantly improved the predicted free energy barrier compared to the original DFTB3 parameters. As a final test, the new parametrization was tested in a small system bearing the 1,4-dihydropyridine core motif of NAD(P)H and using benzyne as a substrate, where it corrected the energy profile provided by the original DFTB3 Hamiltonian, showing the transferability of the new parameters.