Microsecond simulation of human aquaporin 2 reveals structural determinants of water permeability and selectivity

Human aquaporin 2 (AQP2) from the family of aquaporins assumes great physiological importance, owing to its association with nephrogenic diabetes insipidus (NDI). The present study provides detailed insights into the transport properties of AQP2 with the use of microsecond-scale molecular dynamics simulations, and explains how these channels conduct water molecules while at the same time excluding other molecules. Water transport is seen to be diffusion-limited, with a barrier of only 1.6 kcal mol(-1), and the channel is more water-permeable than other known aquaporins. A constriction site with a pore-facing phenylalanine and arginine is proposed to serve as a selectivity filter as well as a gate modulating the conductance state of the channel. Water molecules form a continuous single-file in the pore lumen, and the orientation of water molecules in this chain is governed by water-protein interactions. A mutant is designed that exhibits different orientation of water molecules, leading to altered permeability. The study complements experimental studies by revealing details of the transport mechanism, energetics, and kinetics. Furthermore, insights obtained into the regulation of permeability in the channel offer the promise of devising new strategies for altering the permeability of the channel under diseased conditions. (C) 2016 Elsevier B.V. All rights reserved.