4.5 Article

Challenging AQP4 druggability for NMO-IgG antibody binding using molecular dynamics and molecular interaction fields

Journal

BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
Volume 1848, Issue 7, Pages 1462-1471

Publisher

ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamem.2015.03.019

Keywords

Molecular dynamics; Molecular interaction fields; Aquaporins; Druggability; Molecular docking

Funding

  1. program FIRB (Futuro in Ricerca) [RBFR12SJA8_003]
  2. CINECA under the ISCRA initiative [HP10CL5BLB-hAQP4, HP10B4VZO7-epi-NMO]

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Neuromyelitis optica (NMO) is a multiple sclerosis-like immunopathology disease affecting optic nerves and the spinal cord. Its pathological hallmark is the deposition of a typical immunoglobulin, called NMO-IgG, against the water channel Aquaporin-4 (AQP4). Preventing NMO-IgG binding would represent a valuable molecular strategy for a focused NMO therapy. The recent observation that aspartate in position 69 (D69) is determinant for the formation of NMO-IgG epitopes prompted us to carry out intensive Molecular Dynamics (MD) studies on a number of single-point AQP4 mutants. Here, we report a domino effect originating from the point mutation at position 69: we find that the side chain of T62 is reoriented far from its expected position leaning on the lumen of the pore. More importantly, the strength of the H-bond interaction between L53 and T56, at the basis of the loop A, is substantially weakened. These events represent important pieces of a clear-cut mechanistic rationale behind the failure of the NMO-IgG binding, while the water channel function as well as the propensity to aggregate into OAPs remains unaltered. The molecular interaction fields (MIF)-based analysis of cavities complemented MD findings indicating a putative binding site comprising the same residues determining epitope reorganization. In this respect, docking studies unveiled an intriguing perspective to address the future design of small drug-like compounds against NMO. In agreement with recent experimental observations, the present study is the first computational attempt to elucidate NMO-IgG binding at the molecular level, as well as a first effort toward a less elusive AQP4 druggability. (C) 2015 Elsevier B.V. All rights reserved.

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