We tested GFN2-xTB's performance in describing hydride transfer reactions in CCR and DHFR systems (see Figure ). Using the ASM, we performed QM/MM calculations at the GFN2-xTB/CHARMM36 level of theory (see the SI for details). For both systems, our analysis revealed significant differences in the potential of mean force (PMF) profiles between the semiempirical QM/MM Hamiltonian and the corrected profiles at the M06-2X-D3/def2-TZVP//GFN2-xTB/CHARMM36 level of theory (see the SI for a detailed description of the dual-level correction scheme). The implementation of our proposed methodology for GFN2-xTB's re-parametrization began with generating initial training sets from IRC calculations, followed by executing the MOO strategy to address the observed deficiencies. We refined these new parametrizations through multiple optimization steps, incorporating additional smaller data sets from QM/MM PES scan calculations using both the reference Hamiltonian and partially refined GFN2-xTB parameters. The final converged parameter sets were validated through QM/MM calculations using the ASM. The next subsections detail our results on GFN2-xTB's reparametrization for these hydride transfer reactions.