title: Structure and Dynamics of Extracellular Loops in Human Aquaporin-1 from Solid-State NMR and Molecular Dynamics.
abstract: Multiple moderate-resolution crystal structures of human aquaporin-1 have provided a foundation for understanding the molecular mechanism of selective water translocation in human cells. To gain insight into the interfacial structure and dynamics of human aquaporin-1 in a lipid environment, we performed nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulations. Using magic angle spinning solid-state NMR, we report a near complete resonance assignment of the human aquaporin-1. Chemical shift analysis of the secondary structure identified pronounced deviations from crystallographic structures in extracellular loops A and C, including the cis Y37-P38 bond in loop A, as well as ordering and immobilization of loop C. Site-specific H/D exchange measurements identify a number of protected nitrogen-bearing side chains and backbone amide groups, involved in stabilizing the loops. A combination of molecular dynamics simulations with NMR-derived restraints and filtering based on solvent accessibility allowed for the determination of a structural model of extracellular loops largely consistent with NMR results. The simulations reveal loop stabilizing interactions that alter the extracellular surface of human AQP1, with possible implications for water transport regulation through the channel. Modulation of water permeation may occur as a result of rearrangement of side chains from loop C in the extracellular vestibule of hAQP1, affecting the aromatic arginine selectivity filter.
authors: Department of Physics, University of Guelph , Guelph, ON, Canada N1G 2W1.
authors: Shenlin
authors: S
authors: Wang
authors: Molecular Structure and Function, Hospital for Sick Children , Toronto, ON, Canada M5G 1X8.|Department of Biochemistry, University of Toronto , Toronto, ON, Canada M5S 1A8.
authors: Christopher
authors: C
authors: Ing
authors: Department of Physics, University of Guelph , Guelph, ON, Canada N1G 2W1.|Biophysics Interdepartmental Group, University of Guelph , Guelph, ON, Canada N1G 2W1.
authors: Sanaz
authors: S
authors: Emami
authors: Department of Cell Physiology and Molecular Biophysics, School of Medicine, Texas Tech University Health Sciences Center , Lubbock, Texas 79430, United States.
authors: Yunjiang
authors: Y
authors: Jiang
authors: Department of Cell Physiology and Molecular Biophysics, School of Medicine, Texas Tech University Health Sciences Center , Lubbock, Texas 79430, United States.
authors: Hongjun
authors: H
authors: Liang
authors: Molecular Structure and Function, Hospital for Sick Children , Toronto, ON, Canada M5G 1X8.|Department of Biochemistry, University of Toronto , Toronto, ON, Canada M5S 1A8.
authors: Régis
authors: R
authors: Pomès
authors: Department of Physics, University of Guelph , Guelph, ON, Canada N1G 2W1.|Biophysics Interdepartmental Group, University of Guelph , Guelph, ON, Canada N1G 2W1.
authors: Leonid S
authors: LS
authors: Brown
authors: Department of Physics, University of Guelph , Guelph, ON, Canada N1G 2W1.|Biophysics Interdepartmental Group, University of Guelph , Guelph, ON, Canada N1G 2W1.
authors: Vladimir
authors: V
authors: Ladizhansky
mesh_terms: D051398:Aquaporin 1 / Q000737:chemistry*; D005110:Extracellular Space / Q000737:chemistry*; D006801:Humans; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation
chemical_list: D051398:Aquaporin 1