In this work, we have accelerated the QM/MM interactions through two strategies, i.e., singlecenter and ESPF : i) In the single-center strategy, a single-center multipole expansion is performed on the QM subsystem, and the QM/MM interaction is then computed through the molecular QM multipoles. ii) In the ESPF strategy, the QM/MM interaction is also computed through QM multipoles, but a multicenter ESP-fitted multipole expansion is conducted. More details about the implementation of both studies can be found in Ref. The effect of the order p of the multipole expansion as well as R exact , the cutoff radius beyond which the approximate coupling is used, will be shown in the results section.