Dynamics and energetics of water transport through aquaporin mutants causing nephrogenic diabetes insipidus (NDI): A molecular dynamics study

Human aquaporin-2 (AQP2) is the principal water channel in the human kidney. Any alteration of its physiological functioning may lead to the water imbalance and consequently diseases in humans, especially nephrogenic diabetes insipidus (NDI). Although many of the mutations associated with NDI are experimentally discovered and examined, a molecular level characterization of the structure and transport mechanism is still missing. In this paper, the gating effects of selectivity filter (SF) as wide/narrow states on the mechanism and dynamics of water permeation within the wild-type AQP2 and two NDI causing mutants as AQP2-V168M and AQP2-G64R are studied for the first time. The analysis of the 200 ns trajectory shows that the SF region in AQP2 is not only a selectivity filter, as previously reported but also it performs as a gating site depending on the side-chain conformation of His172. The assignment of the wide/narrow states of SF is supported by computing the free energy and permeability through the AQP2. Moreover, by exploring the effects of V168M and G64R mutants on the AQP2 structure during 200 ns trajectories, remarkable increases of energy barriers are observed in the middle and cytoplasmic side of the pore, respectively. Interestingly, it is found that due to the variable conformations of the SF region as wide/narrow, the effect of the NDI causing mutants on the average water permeability can be revealed with notably better accuracy by finding the wide states in the wild-type and mutated types of AQP2 and comparing the osmotic permeabilities for this state. Communicated by Ramaswamy H. Sarma