The task of adjusting GFN2-xTB or any other semiempirical method's parameters to accurately describe the PES of enzymatic reactions, atomic gradients, and charges is a highly complex, MOO challenge. GFN2-xTB, as a semiempirical method, relies on a parameter set that often includes many tens of adjustable parameters (see more details in the "GFN2-xTB re-parametrization strategy" section in the SI). These parameters must be fine-tuned to ensure that the method can reliably reproduce the energetics and electronic properties observed in HL quantum mechanical calculations.