Our strategy begins with conducting HL single-point calculations in gas phase using the reference HL Hamiltonian (M06-2X-D3/def2-TZVP in this work), for configurations derived from the exploration of the PES along the characterized reaction paths of the target enzymatic reactions (generated from QM or QM/MM calculations). The primary objective of this re-parametrization process is to align semiempirical method's PES profiles with those obtained from HL-based calculations, while simultaneously minimizing discrepancies in atomic gradients and charges. This involves several key considerations: