In this study, we validated our parametrization methodology through limited HL QM/MM sampling. Although computationally intensive, this approach enables direct comparison of structural and energetic properties between simulations using our optimized parameters and HL QM/MM calculations, providing a rigorous assessment of our parametrization scheme. It is important to emphasize that this extensive validation step is not an inherent requirement of the parametrization process -indeed, if HL QM/MM calculations were routinely feasible, semiempirical methods would be unnecessary. Instead, this validation demonstrates the reliability of our parametrization approach for future applications where HL calculations would be computationally prohibitive.