To evaluate the improved DFTB3 Hamiltonian in a more realistic model of the enzymatic environment, we conducted constrained QM/MM geometry optimizations along the reaction coordinate for the hydride transfer reaction using a complete solvated model of the Ccr enzyme. We compared the results of various parameterizations at the DFTB3/CHARMM36 level with single-point calculations at the M06-2X/def2-TZVP/CHARMM36 level. Our calculations showed that, while the different C-H parameterizations agree in addressing the severe energy underestimation at the TS region in the QM/MM model, the CH_4 modification provided a better estimate of the activation energy compared to the DFT-corrected energy profile (see Figure ). As expected, modifying the C-H RPFs does not correct the underestimation in the reaction energy as evidenced before by the IRC calculations. We then tested different combinations of the CH_4 parametrization with CC RPF's modifications, and while we were not able to fully correct the reaction energy compared to the reference calculations, we found that the combination of LCHFs CH_4 with CC_3 provided the most significant improvement in describing the activation barrier (see Figure ), as discussed earlier for the IRC profile.