The adaptive-partitioning (AP) schemes for combined quantum-mechanical/ molecular-mechanical (QM/MM) calculations allow on-the-fly reclassifications of atoms and molecules as QM or MM in dynamics simulations. The permuted-AP (PAP) scheme (J. Phys. Chem. B 2007, 111, 2231) introduces a thin layer of buffer zone between the QM subsystem (also called active zone) and the MM subsystem (also known as the environmental zone) to provide a continuous and smooth transition and expresses the potential energy in a many-body expansion manner. The PAP scheme has been successfully applied to study small molecules solvated in bulk solvent. Here, we propose two modifications to the original PAP scheme to treat solvent molecules entering and leaving protein binding sites. First, the center of the active zone is placed at a pseudoatom in the binding site, whose position is not affected by the movements of ligand or residues in the binding site. Second, the extra forces due to the smoothing functions are deleted. The modified PAP scheme no longer describes a Hamiltonian system, but it satisfies the conservation of momentum. As a proof-of-concept experiment, the modified PAP scheme is applied to the simulations under the canonical ensemble for two binding sites of the Escherichia coli CLC chloride ion transport protein, in particular, the intracellular binding site S int discovered by crystallography and one putative additional binding site S add suggested by molecular modeling. The exchange of water molecules between the binding sites and bulk solvent is monitored. For comparison, simulations are also carried out using the same model system and setup with only one exception: the extra forces due to the smoothing functions are retained. The simulations are benchmarked against conventional QM/MM simulations with large QM subsystems. The results demonstrate that the active zone centered at the pseudo atom is a reasonable and convenient representation of the binding site. Moreover, the transient extra forces are non-negligible and cause the QM water molecules to move out of the active zone. The modified PAP scheme, where the extra forces are excluded, avoids the artifact, providing a realistic description of the exchange of water molecules between the protein binding sites and bulk solvent.