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

被引:16
|
作者
Padhi, Siladitya [1 ]
Priyakumar, U. Deva [1 ]
机构
[1] Int Inst Informat Technol, Ctr Computat Nat Sci & Bioinformat, Hyderabad 500032, Andhra Pradesh, India
来源
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES | 2017年 / 1859卷 / 01期
关键词
Molecular dynamics; Membrane proteins; Water transport; Aquaporin; NEPHROGENIC DIABETES-INSIPIDUS; MOLECULAR-DYNAMICS SIMULATIONS; PROTON EXCLUSION; FORCE-FIELD; CHANNEL; MECHANISM; TRANSPORT; CHARMM; PERMEATION; GLPF;
D O I
10.1016/j.bbamem.2016.10.011
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页码:10 / 16
页数:7
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