In this work, we incorporated MLIPs into the AMBER simulation platform. We then used the modified code to validate conservation laws within the ML/MM approach, thereby ensuring a thermodynamically consistent system. Next, we advanced the theory of free energy calculations using the thermodynamic integration (TI) method with the core part being described by MLIPs. We tested the new technique by preforming hydration free energy calculations via multi-scale ML/MM molecular dynamics simulations. To further explore potential applications of ML/MM MD to macromolecular systems, we applied the ML/MM MD engine to sample conformations and MM-PBSA method to predict binding free energy for a set of protein-ligand complexes. Finally, we performed performance tests on our code. By leveraging advancements in MLIPs and integrating them with multi-scale simulation techniques, we expect that our ML/MM approach can help address many current challenges in molecular simulation.