Figure shows the PMF profiles for the hydride transfer reaction in CCR. As can be appreciated, the PMF profile obtained using the re-parametrized GFN2-xTB Hamiltonian with the CHARMM36 force field (blue curve labeled as BestCCR) closely follows the reference PMF profiles calculated at the M06-2X-D3/def2-SVP/CHARMM36 level within 1 kcal/mol (black curve) and perfectly matches its higher-level corrections to M06-2X-D3/def2-TZVP (red dashed curve). In this case, the new parameters allowed to accurately reproduce the reaction barrier height and the overall shape of the free energy profile, demonstrating its effectiveness in modeling this enzymatic reaction. For DHFR (Figure ), we achieved remarkable results using a streamlined parametrization approach that combined CCR-IRC data with just 40 additional DHFR-specific geometries from scan calculations (DHFR-SC data set). The optimized parameters produced PMF profiles (blue curve labeled as "Best(CCR+DHFR)") that show good agreement with reference calculations at both M06-2X-D3/def2-SVP/CHARMM36 (black curve) and M06-2X-D3/def2-TZVP//def2-SVP/CHARMM36 (red dashed curve) levels, particularly in reproducing the reaction barrier height.