1. Initial QM/MM Setup and Single-Point Calculations: Begin by setting up the QM/MM model of the enzymatic system. This involves defining the QM region, typically including the active site and key residues or co-factors, while the remaining system is described using an appropriate molecular mechanics (MM) force field. Once the QM region is defined, explore the PES using a HL DFT/ab initio method. This exploration can be performed either at the QM/MM level or in vacuum using only the QM region, depending on computational resources and the specific characteristics of the reaction under study. For instance, one can use Hamiltonians like M06-2X-D3/def2-TZVP to perform single-point energy calculations on optimized QM geometries at any of both levels M06-2X-D3/def2-SVP/CHARMM36 or M06-2X-D3/def2-SVP. Since these calculations will serve as reference data for the re-parametrization, it is crucial to choose a validated level of theory appropriate for the system under study.