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

Abstract

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 1.6kcalmol, 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.

Investigation of the aquaporin‐2 gating mechanism with molecular dynamics simulations

“…It is shown that the ar/R region in AQP2 does not only act as a SF, which is already reported in the previous studies, 14,20 but also acts as a gating site. Spontaneous fluctuations at the SF regions of the pores have been investigated and the conformational states of the His172 side chain have been related to the water permeation properties, in particular, key features such as diffuse and osmotic permeabilities and water occupancy.…”

“…Soon after the first molecular study by our group on AQP2 in which the diffusion permeability and osmotic permeability for water transport within AQP2's channels were obtained, 14 Padhi et al examined some other issues including mechanism and energetics. 20 MD simulation has emerged as an important tool for exploring the gating mechanism in AQPs. 10,18,21,22 In this regard, Janosi and Ceccarelli 10 observed that the pores of AQP5 are closed because of different states of histidine in the CE region.…”

Unveiling the Mechanisms of Aquaglyceroporin‐3 Water and Glycerol Permeation by Metadynamics

“…[22] Underneath, the pore centre is defined by two highly conserved asparagine-proline-alanine (NPA) motifs contained in the Ba nd El oops and semi-helices, whicha re responsiblef or exclusion of charged solutes. [31] Further work has been undertaken to understand the free energies involved in permeation eventso fanumber of AQP isoforms, [32,33] providing insight at an atomistic level into the role played by the selectivity filters in water transport. [18,29,30] Size and shapeo ft he pore constrain water orientation and affect internal water-water interactions.…”

“…[18,29,30] Size and shapeo ft he pore constrain water orientation and affect internal water-water interactions. [31] Further work has been undertaken to understand the free energies involved in permeation eventso fanumber of AQP isoforms, [32,33] providing insight at an atomistic level into the role played by the selectivity filters in water transport. Recent studieso nc arbon nanotubes as bio-mimic channels ystems consistently identified an optimal pore size threshold for single-file water transport of 0.8 nm, which significantly affected transport rate and molecular translocation direction.…”

Forced diffusion of water molecules through aquaporin-5 biomembrane; a molecular dynamics study

“…Also the water movement through AqpZ has been studied by MD simulation [17]. Moreover a recent work demonstrated that MD simulation of human AQP2 gives new insightful information about water permeation mechanisms and urine concentration in the human kidney [18,19].…”