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Inhibition of Water Transport in Human Aquaporin-4:
A Combined Molecular Docking and Molecular Dynamics Study
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Debasis Koley, E. Matthias Müller , Bert L. de Groot and Helmut Grubmüller
The aquaglyceroporin superfamily consists of membrane proteins that primarily facilitate the passive diffusion of water and other small neutral molecules (e.g. glycerol) [1]. Members of this family are found throughout nature, in species ranging from bacteria to humans, and more than 350 proteins have been identified and sequenced so far. Aquaporin-4 (AQP4) is a part of this family which resides in the mammalian brain and functions as a predominant water channel. Like other aquaporins, AQP4 are extremely permeable to water but prevent the passage of any other solutes, particularly ions and protons. Malfunctioning of this water-channel can trigger diseases like cerebral edema, bipolar disorder and mesial temporal lobe epilepsy [2].
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Motivation
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Excessive water uptake through AQP4 can be detrimental and hence reversible inhibitors are required to bind at specific site of the channel and block the water passage. Recent experimental findings elucidate the function of TEA (tetraethylammonium) as a lead compound in blocking aquaporin water permeability (for AQP1 and AQP4). Furthermore, multi-nanosecond molecular dynamics (MD) simulations are performed to corroborate and explain the experimental findings [3].
The results from the simulation indicates that TEA interacts with the charged residues in the C (Asp128) and E (Asp185) loop, and the A (Tyr37-Asn42-Thr44) loop of the neighboring monomer [3].
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Simulation & Setup
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Homology modeling by WHAT-IF package [4].
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Periodic box with tetrameric hAQP4, 271 POPE and 16892 TIP4P water molecules.
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OPLS, all-atom force field.
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GROMACS 3.3.1 version [5].
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PME for electrostatics.
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Lincs and Settle to constrain covalent bond
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MD equilibration for 20ns.
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Preliminary MD-results
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Hiroaki et al. have recently determined the rat AQP4 (rAQP4) structure by electron crystallography of double-layered, two-dimensional (2D) crystals [4]. The human AQP4 (hAQP4) was homology modeled from rAQP4 having a sequence identity of ~ 94%. The modeled structure was equilibrated using MD simulation (20ns) and the subsequent trajectory was dedicated for further investigations.
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Figures 4 (a, b) represent the RMSD plot of the protein and the relative fluctuations of the residues in chain A (color blue in Figure 1).
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A and C-loop reveals greater flexibility
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Rough visualization of the cavity surface through the monomer pore (Figure 4c) [6]. The pore radius plotted along the pore axis reveals ar/R region (Arg186) as the most narrowest (Figure 4d).
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The number of water molecules passing through the NPA and ar/R region are reduced (Figure 4e).
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Preliminary Docking Results:
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Representative snapshots from the last 5 ns trajectory were used for docking simulations [7].
Figure 5 (a, b, c) represents different docked conformations of the TEA inhibitor on hAQP4.
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The TEA (blue) interacts with A loops of chain B and neighboring chain C respectively. In chain A the TEA (red) directly interacts with Try177 (Figure 5a).
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Important interactions are visible with residues Glu257, Val262 from chain B and Pro485, Asp487 from chain C.
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Conclusions
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We have performed preliminary docking studies of TEA on tetrameric hAQP4. The different binding regimes are characterized
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Further investigations are in progress in order to illuminate the interaction at the specific binding site and binding affinity at an atomistic level.
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References
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(a) P. Agre, Angew. Chem. Int. Ed. 2004, 43, 4278. (b) K. Murata, K. Mitsuoka, T. Hirai, T. Walz, P. Agre, J. B. Heymann, A. Engel, Y. Fujiyoshi, Nature 2000, 407, 599.
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Y. Hiroaki, K. Tani, A. Kamega, N. Gyobu, K. Nishikawa, H. Suzuki, T. Walz, S. Sasaki, K. Mitsuoka, K. Kimura, A. Mizoguchi, Y. Fujiyoshi, J. Mol. Biol. 2006, 355, 628.
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F. J. M. Detmers, B. L. de Groot, E. M. Müller, A. Hinton, I. B. M. Konings, M. Sze, S. L. Flitsch, H. Grubmüller, P. M. T. Deen, J. Biol. Chem. 2006, 281, 14207.
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(a) D. Van der Spoel, E. Lindahl, B. Hess, G. Groenhof, A. E. Mark, H. J. C. Berendsen, J. Comp Chem. 2005, 26, 701. (b) E. Lindahl, B. Hess, D. Van der Spoel, J. Mol. Model. 2001, 7, 306.
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