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. 2011 Sep 9;412(4):654-9.
doi: 10.1016/j.bbrc.2011.08.019. Epub 2011 Aug 12.

Water transport in human aquaporin-4: molecular dynamics (MD) simulations

Yubao Cui  1 , David A Bastien
Affiliations

Water transport in human aquaporin-4: molecular dynamics (MD) simulations

Yubao Cui et al. Biochem Biophys Res Commun. .

Abstract

Aquaporin-4 (AQP4) is the predominant water channel in the central nervous system, where it has been reported to be involved in many pathophysiological roles including water transport. In this paper, the AQP4 tetramer was modeled from its PDB structure file, embedded in a palmitoyl-oleoyl-phosphatidyl-choline (POPC) lipid bilayer, solvated in water, then minimized and equilibrated by means of molecular dynamics simulations. Analysis of the equilibrated structure showed that the central pore along the fourfold axis of the tetramers is formed with hydrophobic amino acid residues. In particular, Phe-195, Leu-191 and Leu-75, form the narrowest part of the pore. Therefore water molecules are not expected to transport through the central pore, which was confirmed by MD simulations. Each monomer of the AQP4 tetramers forms a channel whose walls consist mostly of hydrophilic residues. There are eight water molecules in single file observed in each of the four channels, transporting through the selectivity filter containing Arg-216, His-201, Phe-77, Ala-210, and the two conserved Asn-Pro-Ala (NPA) motifs containing Asn-213 and Asn-97. By using Brownian dynamics fluctuation-dissipation-theorem (BD-FDT), the overall free-energy profile was obtained for water transporting through AQP4 for the first time, which gives a complete map of the entire channel of water permeation.

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Figures

Fig. 1
Fig. 1
The RMSD for one of the monomers during the equilibrium molecular dynamics simulations. The RMSD of the protein heavy atoms (hydrogen atoms are excluded) is shown in green, the RMSD of the protein backbone is shown in red. (For interpretation of the references in color in this figure legend, the reader is referred to the web version of this article.)
Fig. 2
Fig. 2
The water-conducting channel of one monomer of AQP4. (A) The overall architecture, the protein is shown in NewCartoon and important residues in Licorice drawing method, water molecules in VDW; (B) the extracellular vestibule, formed by Thr-56, Ile-73, Ile-205, Gly-209, Thr-148 and Gly-146, depicted in Licorice drawing method and water molecules in VDW; (C) the selectivity filter, formed by Arg-216, His-201, Phe-77 and Ala-210, depicted in Licorice drawing method and water molecules in VDW; (D) Asn-213, a member of the NPA motif, which interacts with water molecules in the conducting channel. Residues Asn-213, Val-197, Phe-48, and Met-212 are depicted in Licorice drawing method and water molecules in VDW; (E) Asn-97, a member of the other NPA motif, which interact with water molecules in the conducting channel. Residues Asn-97, Ile-96, Ile-81 and Leu-170 are depicted in Licorice drawing method and water in VDW; (F) His-95, which interact with water molecules in the conducting channel. Residues His-95, Val-100, Val-85 and Ile-193 are depicted in Licorice drawing method and water in VDW.
Fig. 3
Fig. 3
The dimension of the conducting channel's inner surface calculated using the Hole 2.0 program.
Fig. 4
Fig. 4
The work curves and the free-energy profile of water permeation through the channels of AQP4. (A) Work done along the forward and reverse pulling paths. Using the last frame, four water molecules were pulled from start position at 10 Å to –30 Å through AQP4 channels, one water molecule through each channel, and five forward and five reverse paths were performed. The work is average over the four water molecules pulled through the four channels simultaneously. (B) The free-energy profile of AQP4 was computed by using the Brownian dynamics fluctuation–dissipation-theorem (BD-FDT) method according to the mechanical work done along the above pulling paths. The origin of the coordinate system is so chosen that marked for the selectivity filter (SF) NPA motifs.
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References

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