Dynamic hydration valve controlled ion permeability and stability of NaK channel

The K^+^, Na^+^, Ca^2+^ channels are essential to neural signalling, but our current knowledge at atomic level is mainly limited to that of K^+^ channels. Unlike a K^+^ channel having four equivalent K^+^-binding sites in its selectivity filter, a NaK channel conducting both Na^+^ and K^+^ ions has a vestibule in the middle part of its selectivity filter, in which ions can diffuse but not bind specifically. However, how the NaK channel conducts ions remains elusive. Here we find four water grottos connecting with the vestibule of the NaK selectivity filter. Molecular dynamics and free energy calculations show that water molecules moving in the vestibule-grotto complex hydrate and stabilize ions in the filter and serve as a valve in conveying ions through the vestibule for controllable ion permeating. During ion conducting, the water molecules are confined within the valve to guarantee structure stability. The efficient exquisite hydration valve should exist and play similar roles in the large family of cyclic nucleotide-gated channels which have similar selectivity filter sequences. The exquisite hydration valve mechanism may shed new light on the importance of water in neural signalling