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Aquaporin-2 plays a vital role in the human kidney as a water passage channel. Any disorder with its function can cause water imbalance and consequently disease in humans, especially nephrogenic diabetes insipidus (NDI). For this reason, an accurate understanding of its performance can be useful for therapeutic purposes. In this article, we investigate the gating mechanism induced by spontaneous fluctuations in aquaporin-2's (AQP2) channels in the palmitoyl-oleoyl-phosphatidyl-ethanolamine lipid bilayer by molecular dynamics. Our results show that the selectivity filter (SF) in AQP2 is also a gating site depending on the side-chain conformation of His172. The important role of His172 in modulating the wide and narrow conformations has been further investigated by the simulation of the H172G mutant. The osmotic permeability values of all four monomers are in the range of wide state and the average is very close to that of the wide channel formed by wild-type AQP2. Moreover, by calculating the osmotic permeability and the potential of mean force of each of the AQP2 monomers for wide/narrow states of the SF, it is seen that the SF at its narrow conformation can induce a much larger energy barrier for water molecules permeation, hindering the transport of water molecules remarkably. The reason for the discrepancy among osmotic permeabilities of different monomers of aquaporins is revealed by investigating the osmotic permeability of each monomer through the wide/narrow states of their SF.

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