TCB Publications - Abstract

Jihong Tong, Zhe Wu, Margaret M. Briggs, Klaus Schulten, and Thomas J. Mclntosh. The water permeability and pore entrance structure of aquaporin-4 channels depend on lipid bilayer thickness. Biophysical Journal, 111:90-99, 2016. (PMC:  PMC4944661)

TONG2016 Aquaporin-4 (AQP4), the primary water channel in glial cells of the mammalian brain, plays a critical role in water transport in the central nervous system. Previous experiments have shown that the water permeability of AQP4 depends on the cholesterol content in the lipid bilayer, but it was not clear whether these changes were due to direct cholesterol-AQP4 interactions, or due to indirect effects caused by cholesterol-induced changes in bilayer elasticity or bilayer thickness. To determine the effects resulting only from bilayer thickness, here we use a combination of experiments and simulations to analyze AQP4 in cholesterol-free phospholipid bilayers with similar elastic properties, but different hydrocarbon core thicknesses previously determined by X-ray diffraction. The channel (unit) water permeabilities of AQP4 measured by osmotic gradient experiments were 3.5 $\pm$ 0.2 x 10$^{-13}$ cm$^3$/sec (mean $\pm$ SEM), 3.0 $\pm$ 0.3 x 10$^{-13}$ cm$^3$/sec, 2.5 $\pm$ 0.2 x 10$^{-13}$ cm$^3$/sec, 0.9 $\pm$ 0.1 x 10$^{-13}$ cm$^3$/sec in bilayers containing (C22:1)(C22:1)PC, (C20:1)(C20:1)PC, (C16:0)(C18:1)PC, and (C13:0)(C13:0)PC, respectively. Channel permeabilities obtained by molecular dynamics (MD) simulations were 3.3 $\pm$ 0.1 x 10${-13}$ cm$^3$/sec and 2.5 $\pm$ 0.1 x 10$^{-13}$ cm$^3$/sec in (C22:1)(C22:1)PC and (C14:0)(C14:0)PC bilayers, respectively. Both the osmotic gradient and MD simulation results indicated that AQP4 channel permeability decreased with decreasing bilayer hydrocarbon thickness. The MD simulations were also used to determine structural modifications in AQP4 in response to changes in bilayer thickness. Although the simulations showed no appreciable changes to the radius of the pore located in the hydrocarbon region of the bilayers, the simulations demonstrated changes both in pore length and alpha helix organization near the cytoplasmic vestibule of the channel. These structural changes, caused by mismatch between the hydrophobic length of AQP4 and the bilayer hydrocarbon thickness, could explain the observed differences in water permeability with changes in bilayer thickness.

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