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. 2010 Feb 15;78(3):661-70.
doi: 10.1002/prot.22595.

Nitric oxide conduction by the brain aquaporin AQP4

Yi Wang  1 , Emad Tajkhorshid
Affiliations

Nitric oxide conduction by the brain aquaporin AQP4

Yi Wang et al. Proteins. .

Abstract

Involvement of aquaporins in gas conduction across the membrane and the physiological significance of this process have attracted marked attention from both experimental and theoretical studies. Previous work demonstrated that AQP1 is permeable to both CO(2) and O(2). Here we employ various simulation techniques to examine the permeability of the brain aquaporin AQP4 to NO and O(2) and to describe energetics and pathways associated with these phenomena. The energy barrier to NO and O(2) permeation through AQP4 central pore is found to be only approximately 3 kcal mol(-1). The results suggest that the central pore of AQP4, similar to that of AQP1, can indeed conduct gas molecules. Interestingly, despite a longer and narrower central pore, AQP4 appears to provide an energetically more favorable permeation pathway for gas molecules than AQP1, mainly due to the different orientation of its charged residues near the pore entrance. Although the low barrier against gas permeation through AQP4 indicates that it can participate in gas conduction across the cellular membrane, physiological relevance of the phenomenon remains to be established experimentally, particularly since pure lipid bilayers appear to present a more favorable pathway for gas conduction across the membrane. With an energy well of -1.8 kcal mol(-1), the central pore of AQP4 may also act as a reservoir for NO molecules to accumulate in the membrane.

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Figures

Figure 1
Figure 1
Simulation systems. Side view (a) and top view (b) of the explicit gas diffusion simulation system. The AQP4 tetramer is embedded in a lipid bilayer (head group: brown, tail: green), with the four monomers colored in yellow, orange, cyan, and black, respectively. 150 NO molecules are placed in the bulk water, ~10 Å away from the membrane. Water is shown as a transparent box. (c) Close-up view of the umbrella sampling simulation system. The central pore is divided into 33 windows, with the center of each window represented by a black line. While most windows are placed ~1 Å apart, more are added near the two entrances of the central pore (Leu66 and Leu191) to improve sampling in these narrow regions.
Figure 2
Figure 2
Explicit gas diffusion simulation results. (a) Seven NO molecules entered the central pore of AQP4 spontaneously in the 50-ns explicit gas diffusion simulation. (b) NO molecules also entered the water pore spontaneously. However, no NO molecule is observed in the selectivity filter (Arg216, Phe77 and His201), which is the narrowest region of the water pore.
Figure 3
Figure 3
PMF of NO and O2 permeation through AQP4 and a POPE bilayer. (a) PMF of NO permeation through AQP4 central pore (NO−cp) and water pores (NO−wp), calculated using both umbrella sampling (US) and implicit ligand sampling (ILS). (b) Enthalpic contributions (ΔEtot) to the PMF of NO permeation (NO−cp(US)), calculated from interaction energy of NO with protein (ΔEpro), and with water (ΔEwat). (c) PMF of O2 permeation through AQP4. (d) PMF of NO and O2 permeation through a POPE bilayer. In all PMFs, z = 0 is set to the center-of-mass of the AQP4 tetramer or the center of the bilayer. The reference point of all PMFs is vacuum, except for (b) (see Methods).
Figure 4
Figure 4
Comparison of AQP4 and AQP1 central pores. (a) Superposition of AQP4 (blue) and AQP1 (orange). The transmembrane helix H2 in AQP4 extends an extra turn, making the central pore ~10 Å longer than that of AQP1. (b) Radii of AQP4 and AQP1 central pores calculated based on their crystal structures using the program HOLE (72). Residues Leu66 in AQP4 and Val52 in AQP1 correspond to the narrowest part in the periplasmic entrance of the two central pores. (c,d) The water occupancy in the periplasmic entrance of the AQP1 (c) and AQP4 (d) central pores. Shown in blue is the volume occupied by water during ≥75% time of the respective simulation. Approximate positions of the central pores are shown using dashed circles. Residues Asp69 in AQP4 relocate the high density water layer to the periphery of the central pore, leaving its entrance “clear”.
Figure 5
Figure 5
Multiple pathways for gas permeation through the central pore. (a) and (b) Two representative pathways revealed by the explicit gas diffusion simulation. The central pore is shown in transparent gray surface. Snapshots of a NO molecule taken every 50–150 ps are shown in red and blue sticks, with its trajectory shown using green lines. To highlight the entry of NO into the central pore, gas molecules from the first few snapshots are drawn using thick sticks, with their trajectories shown in thick green lines. (c) The existence of multiple pathways revealed by implicit ligand sampling. The 2 kcal/mol energy isosurface of the 3D PMF is shown in purple.
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