Population shift between the open and closed states changes the water permeability of an Aquaporin Z mutant

Abstract

Aquaporins are tetrameric transmembrane channels permeable to water and other small solutes. Wild-type (WT) and mutant Aquaporin Z (AqpZ) have been widely studied and multiple factors have been found to affect their water permeability. In this study, molecular dynamics simulations have been performed for the tetrameric AqpZ F43W/H174G/T183F mutant. It displayed ∼10% average water permeability compared to WT AqpZ, which had been attributed to the increased channel lumen hydrophobicity. Our simulations, however, show a ring stacking between W43 and F183 acting as a secondary steric gate in the triple mutant with R189 as the primary steric gate in both mutant and WT AqpZ. The double gates (R189 and W43-F183) result in a high population of the closed conformation in the mutant. Occasionally an open state, with diffusive water permeability very close to that of WT AqpZ, was observed. Taken together, our results show that the double-gate mechanism is sufficient to explain the reduced water permeability in the mutant without invoking effects arising from increased hydrophobicity of the channel lumen. Our findings provide insights into how aquaporin-mediated water transport can be modulated and may further point to how aquaporin function can be optimized for biomimetic membrane applications.

Figure 1

Distance between Arg-189NH1 and A117O, D_oh, as a function of time (A and B). Cumulative water passing events as a function of simulation time (C and D). A and C are from trajectory 1, B and D are from trajectory 2. P1-4 denotes the single channel in the tetramer.

Figure 2

Occurrence distribution of D_oh and the distance between the rings from W43 and F183 side chains, D_WF, for the closed (A) and open state (B) based on all simulation data. The color scale is based on the logarithm of the occurrence counts.

Figure 3

Distribution of distance between the rings of W43 and F183 side chain, D_WF, under the condition of open (red bars) and closed (gray bars) R189-gate based on all simulation data.

Figure 4

Side-chain conformation and HOLE representation of the channel around the SF region for a WF-gate closed configuration (A) and an open water channel (B). Water permeation pathway through the SF region (C). Water molecules hopping between the hydrogen bond acceptors in the SF region.

Figure 5

Distribution of the minimum radius value of water channel under the condition of open (red bars) and closed (gray bars) channel based on all simulation data.