4. Validation of GFN2-xTB's optimized parameters: Following the parametrization process, we can assess the performance of the optimized parameters through several validation approaches. The selection of validation methods depends on both the study's specific objectives and available computational resources. These validation strategies may include: i) performing QM/MM simulations with the optimized parameters and comparing the calculated reaction barriers and structural features of stationary states against experimental data when available, ii) implementing the dual-level correction scheme to evaluate how well the semiempirical PMF profiles align with HL reference calculations, and/or iii) conducting limited HL QM/MM sampling along the reaction coordinate to directly assess the accuracy of the parametrization.