title: Challenging AQP4 druggability for NMO-IgG antibody binding using molecular dynamics and molecular interaction fields.
abstract: 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.
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Via Orabona, 4, Università di Bari "Aldo Moro", Bari, Italy.
authors.forename: Giuseppe Felice
authors.initials: GF
authors.lastname: Mangiatordi
authors.affiliation: Dipartimento Interateneo di Fisica "M. Merlin", Università di Bari "Aldo Moro" and INFN, Via E. Orabona, 4, I-70126 Bari, Italy; Centro Ricerche TIRES, University of Bari "Aldo Moro", Via Amendola 173, I-70126 Bari, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Alberga
authors.affiliation: Molecular Discovery Limited, 215 Marsh Road, Pinner, Middlesex, London HA5 5NE, UK.
authors.forename: Lydia
authors.initials: L
authors.lastname: Siragusa
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Goracci
authors.affiliation: Dipartimento Interateneo di Fisica "M. Merlin", Università di Bari "Aldo Moro" and INFN, Via E. Orabona, 4, I-70126 Bari, Italy; Centro Ricerche TIRES, University of Bari "Aldo Moro", Via Amendola 173, I-70126 Bari, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Lattanzi
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Via Orabona, 4, Università di Bari "Aldo Moro", Bari, Italy; Centro Ricerche TIRES, University of Bari "Aldo Moro", Via Amendola 173, I-70126 Bari, Italy. Electronic address: orazio.nicolotti@uniba.it.
authors.forename: Orazio
authors.initials: O
authors.lastname: Nicolotti
mesh_terms: D051401:Aquaporin 4 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001224:Aspartic Acid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D007074:Immunoglobulin G / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D007930:Leucine / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D009471:Neuromyelitis Optica / Q000276:immunology / Q000378:metabolism; D017354:Point Mutation; D011485:Protein Binding; D013912:Threonine / Q000737:chemistry / Q000378:metabolism
chemical_list: C496030:AQP4 protein, human; D051401:Aquaporin 4; D000939:Epitopes; D007074:Immunoglobulin G; D013912:Threonine; D001224:Aspartic Acid; D007930:Leucine
keywords: Aquaporins; Druggability; Molecular docking; Molecular dynamics; Molecular interaction fields