We employed ANI-2x, which showed its accurate reproduction of DFT results and high reliability, as the MLIP model in the ML/MM MD approach and used cMD as a reference to conduct a 1 nanosecond (ns) simulation with a timestep of 0.1 femtosecond (fs). For the ML/MM simulation, the average energy was -255.28 kcal/mol (Figure ), with a standard deviation of 0.03 kcal/mol, while the cMD simulation showed an average energy of -153.75 kcal/mol (Figure ), with a standard deviation of 0.12 kcal/mol. The difference in the absolute values of the total energy arose because, in the ML/MM approach, the atoms in the ML region are calculated using the MLIP rather than molecular mechanics. Notably, the ML/MM approach demonstrates a lower deviation in energy throughout the simulation, indicating MLIP can reduce the fluctuation of potential energy. By describing a portion of these atoms with MLIP, the computational error from the MM region is minimized. Specifically, in the ML region, the ANI-2x model's potential surface is smooth and nearly consistent, resulting in a balanced net force that helps the ML/MM simulation adhere strictly to the conservation of energy law. Regarding momentum conservation, two simulations were initiated from the same minimized structure, with the initial momentum being set to zero. Throughout the simulations, the velocity of the center of mass remained close to zero: 0.02 for ML/MM (Figure ) and 0.01 for cMD (Figure ), respectively. Neither system was subjected to any external forces, as evidenced by the small fluctuations observed. To further support this observation, we also calculated the translational and rotational energies of both systems. The translational energy remained below 0.15 kcal/mol for both systems (Figure ), while the rotational energy was much lower, at 0.02 kcal/mol for ML/MM and 0.07 kcal/mol for cMD. These findings indicate that the ML/MM approach can consistenly simulate the thermodynamics of a system and produce molecular behaviors without obeying laws of thermodynamics.