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Excessive water uptake through aquaporins can be life threatening, and disregulation of water permeability causes many diseases. Therefore, reversible aquaporin inhibitors are highly desired. In this paper, we identified the binding site for tetraethylammonium (TEA) of the membrane water channel aquaporin-1 by a combined molecular docking and molecular dynamics simulation approach. The binding site identified from docking studies was independently confirmed with an unbiased molecular dynamics simulation of an aquaporin tetramer embedded in a lipid membrane, surrounded by a 100-mM tetraethylammonium solution in water. A third independent assessment of the binding site was obtained by umbrella sampling simulations. These simulations, in addition, revealed a binding affinity of more than 17 kJ/mol, corresponding to an IC(50) value of < 3 mM. Finally, we observed in our simulations a 50% reduction of the water flux in the presence of TEA, in agreement with water permeability measurements on aquaporin expressed in oocytes. These results confirm TEA as a putative lead for an aquaporin-1 inhibitor.
Fig. 1. a Simulation system of an hAQP1 tetramer (green, gray, red, and yellow space-filling representation) embedded in a POPE lipid bilayer (gray) and surrounded by water (red, white). b Starting positions for TEA_dockMD as described in the text. The tetramer is represented as cartoons and TEA in space-filling representation. c Starting positions for TEA_20random. Twenty TEA molecules were randomly placed in the bulk water. d TEA binding site defined via the distribution of TEA nitrogen positions obtained from TEA_dockMD (gray spheres), TEA_20random (magenta spheres), and umbrella sampling (orange spheres)
Fig. 2. Potential of mean force for TEA binding along the channel axes in the upper vestibule of the water pore. The inset shows IC50 values computed from PMFs for different equilibration times. For a detailed description, see text
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