In the case of the CCR-IRC data set, the optimal parameters for DHFR system accurately reproduced the PES of the HL reference data as well as closely matching the results for the BestCCR starting point, introducing minimal improvements. In the case of the DHFR-SC data set, the original GFN2-xTB parametrization exhibits an artificial minimum in the tran-sition state region, which is alleviated even when using the initial parameters from the CCR system optimization. This demonstrates that these parameters are well-suited for qualitatively describing the PES of DHFR. Furthermore, the optimal parameters for DHFR system (step 8) provide a significantly improved fit to the HL reference data, reproducing the PES within 2 kcal/mol.