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.
Comparative Molecular Dynamics Study of Neuromyelitis Optica-Immunoglobulin G Binding to Aquaporin-4 Extracellular Domains
Trisciuzzi, Daniela;Lattanzi, Gianluca;Mangiatordi, Giuseppe;Nicolotti, Orazio
2017-01-01
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.File | Dimensione | Formato | |
---|---|---|---|
87_Nico_BBA_2017.pdf
accesso aperto
Tipologia:
Documento in Versione Editoriale
Licenza:
NON PUBBLICO - Accesso privato/ristretto
Dimensione
2.26 MB
Formato
Adobe PDF
|
2.26 MB | Adobe PDF | Visualizza/Apri |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.