In this study, we implemented the ML/MM approach within the Amber software suite and used it to validate the conservation of energy and momentum. This demonstrates that the ML region and MM region can exchange energy harmoniously, underscoring the robustness of our implementation. Notably, we proposed a new thermodynamic integration protocol for applying ML/MM mixed potentials in alchemical free energy calculations. This development offers new insights in biomolecular systems via high accurate and efficient free energy simulations enabled by multi-scale ML/MM potentials. Additionally, the high quality samplings by mutli-scale ML/MM MD is achieved as the crystal structure properties can bve very well predicted. Combining ML/MM MD sampling with the MM-PBSA endpoint free energy method, we are able to very well predict the binding free energies of a series of compounds binding to a receptor. Thus our approach can integrate seamlessly with other advanced methodologies to expand its functionality. Last, performance testing indicates that the ML/MM approach is a promising method for simulating molecular systems which can achieve a nanosecond per day sampling speed for a typical biological system in drug design.