In our previous study of the hydride transfer step in Ccr, we observed a severe underestimation of the free energy barrier in the reductive carboxylation mechanism when employing QM/MM MD simulations with the DFTB3 method and the 3OB-3-1 parameters set, which required correction at a higher level of theory. In this study, we recalculated the free energy profile for this step using a smaller QM region (see Figure ), observing a similar behavior, which we also corrected using single-point calculations at the DFT level. To address these shortcomings and enhance the predictive accuracy of DFTB3 for studying Ccr's hydride transfer without relying on a posteriori corrections, we developed an approach based on the analysis of structural changes along the reaction path to guide the fitting process of the RPs. We validated the effectiveness of our proposed modifications by performing QM/MM molecular dynamics simulations at the M06-2X/def2-SVP/CHARMM36 level of theory.