Comparative molecular dynamics study of neuromyelitis optica-immunoglobulin G binding to aquaporin-4 extracellular domains

Biochim Biophys Acta Biomembr. 2017 Aug;1859(8):1326-1334. doi: 10.1016/j.bbamem.2017.05.001. Epub 2017 May 3.

Abstract

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system in which most patients have serum autoantibodies (called NMO-IgG) that bind to astrocyte water channel aquaporin-4 (AQP4). A potential therapeutic strategy in NMO is to block the interaction of NMO-IgG with AQP4. Building on recent observation that some single-point and compound mutations of the AQP4 extracellular loop C prevent NMO-IgG binding, we carried out comparative Molecular Dynamics (MD) investigations on three AQP4 mutants, TP137-138AA, N153Q and V150G, whose 295-ns long trajectories were compared to that of wild type human AQP4. A robust conclusion of our modeling is that loop C mutations affect the conformation of neighboring extracellular loop A, thereby interfering with NMO-IgG binding. Analysis of individual mutations suggested specific hydrogen bonding and other molecular interactions involved in AQP4-IgG binding to AQP4.

Keywords: Aquaporin-4; Molecular Dynamics; Mutations; Neuromyelitis Optica.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Aquaporin 4 / chemistry*
  • Aquaporin 4 / immunology
  • Autoantibodies / chemistry*
  • Binding Sites
  • Epitopes / chemistry*
  • Humans
  • Hydrogen Bonding
  • Immunoglobulin G / chemistry*
  • Lipid Bilayers / chemistry
  • Models, Molecular
  • Molecular Dynamics Simulation*
  • Mutation
  • Neuromyelitis Optica / immunology
  • Neuromyelitis Optica / metabolism
  • Neuromyelitis Optica / pathology
  • Phosphatidylcholines / chemistry
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Interaction Domains and Motifs
  • Protein Multimerization
  • Thermodynamics

Substances

  • AQP4 protein, human
  • Aquaporin 4
  • Autoantibodies
  • Epitopes
  • Immunoglobulin G
  • Lipid Bilayers
  • Phosphatidylcholines
  • 1-palmitoyl-2-oleoylphosphatidylcholine