Our work represents a significant step forward in the accurate and efficient modeling of hydride transfer reactions in enzymatic systems using semi-empirical methods for extended sampling. Since activation barriers are often the most crucial energetic feature in enzyme catalysis studies, our approach enables reliable free energy calculations without requiring computationally expensive post-correction with higher-level methods. We expect that the improved DFTB3 parametrization will accelerate research in enzyme engineering, drug design, and the development of bio-inspired catalysts by providing a more efficient computational approach with DFT-level accuracy for the critical aspects of these important reactions.