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.