  Aquaporins (AQPs) are recognized as transmembrane water channels that
facilitate selective water permeation through their monomeric pores. Among the
AQP family, AQP6 has a unique characteristic as an anion channel, which is
allosterically controlled by pH conditions and is eliminated by a single amino
acid mutation. However, the molecular mechanism of anion permeation through
AQP6 remains unclear. Using molecular dynamics simulations in the presence of a
transmembrane voltage utilizing an ion concentration gradient, we show that
chloride ions permeate through the pore corresponding to the central axis of
the AQP6 homotetramer. Under low pH conditions, a subtle opening of the
hydrophobic selective filter (SF), located near the extracellular part of the
central pore, becomes wetted and enables anion permeation. Our simulations also
indicate that a single mutation (N63G) in human AQP6, located at the central
pore, significantly reduces anion conduction, consistent with experimental
data. Moreover, we demonstrate the pH-sensing mechanism in which the
protonation of H184 and H189 under low pH conditions allosterically triggers
the gating of the SF region. These results suggest a unique pH-dependent
allosteric anion permeation mechanism in AQP6 and could clarify the role of the
central pore in some of the AQP tetramers.
