The estimated CPU times of obtaining PMF at the BLYP-D3 level with direct QM/MM and RPM are shown in Table . The CPU time of the RPM includes two parts, i.e. the CPU time for collecting the trajectories at the PM6/MM level and the CPU time for the single point energy calculations at both the PM6/MM and BYLP-D3/MM level. While the direct QM/MM method at the BLYP-D3/MM level only requires the time for the simulations.