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

Alberga, Domenico; Trisciuzzi, Daniela; Lattanzi, Gianluca; Bennett, Jeffrey L.; Mangiatordi, Giuseppe Felice

doi:10.1016/j.bbamem.2017.05.001

Cited by 10 publications

(8 citation statements)

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“…A total of 313 PSGs ( Tables S14 and S15 ) were found in the Yangtze finless porpoise lineage. Our analysis revealed that several PSGs are associated with osmotic adjustment, including aquaporin 4 ( AQP4 ), cystic fibrosis transmembrane conductance regulator ( CFTR ), and guanylate cyclase activator 2B ( GUCA2B ) [ 40 , 41 , 42 ]. AQP4 encodes a member of the aquaporin family of intrinsic membrane proteins, which regulates body water balance.…”

Section: Materials and Methods Results And Discussionmentioning

confidence: 99%

Genome Sequence of the Freshwater Yangtze Finless Porpoise

Yuan

Zhang

Wang

et al. 2018

Genes

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The Yangtze finless porpoise (Neophocaena asiaeorientalis ssp. asiaeorientalis) is a subspecies of the narrow-ridged finless porpoise (N. asiaeorientalis). In total, 714.28 gigabases (Gb) of raw reads were generated by whole-genome sequencing of the Yangtze finless porpoise, using an Illumina HiSeq 2000 platform. After filtering the low-quality and duplicated reads, we assembled a draft genome of 2.22 Gb, with contig N50 and scaffold N50 values of 46.69 kilobases (kb) and 1.71 megabases (Mb), respectively. We identified 887.63 Mb of repetitive sequences and predicted 18,479 protein-coding genes in the assembled genome. The phylogenetic tree showed a relationship between the Yangtze finless porpoise and the Yangtze River dolphin, which diverged approximately 20.84 million years ago. In comparisons with the genomes of 10 other mammals, we detected 44 species-specific gene families, 164 expanded gene families, and 313 positively selected genes in the Yangtze finless porpoise genome. The assembled genome sequence and underlying sequence data are available at the National Center for Biotechnology Information under BioProject accession number PRJNA433603.

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Section: Materials and Methods Results And Discussionmentioning

confidence: 99%

Genome Sequence of the Freshwater Yangtze Finless Porpoise

Yuan

Zhang

Wang

et al. 2018

Genes

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“…All MD simulations were performed using NAMD 2.10 ( Phillips et al, 2005 ) and the CHARMM36 force field ( Best et al, 2012 ). The full system was minimized and in order to remove steric clashes in the initial geometry, we applied a minimization and equilibration protocol consisting of four phases and reported in recent co-authored papers ( Alberga et al, 2014 ; Alberga et al, 2017 ): i ) minimization (2,500 steps) applying harmonic restraints (force constant k = 1 kcal mol −1 Å −2 ) on the protein atoms; 2 ) equilibration at T = 310 K with protein atoms kept at fixed positions for 200 ps; 3) relaxing at T = 310 K for 200 ps by applying harmonic restraints only to the protein atoms (force constant k = 1 kcal mol −1 Å −2 ); 4) gradual heating from T = 10–310 K, increasing the temperature of 25 K every 40 ps. The SHAKE algorithm was employed to constrain all R–H bonds ( Kräutler et al, 2001 ).…”

Section: Methodsmentioning

confidence: 99%

Structural Characterization of the Full-Length Anti-CD20 Antibody Rituximab

Belviso

Mangiatordi

Alberga

et al. 2022

Front. Mol. Biosci.

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Rituximab, a murine–human chimera, is the first monoclonal antibody (mAb) developed as a therapeutic agent to target CD20 protein. Its Fab domain and its interaction with CD20 have been extensively studied and high-resolution atomic models obtained by X-ray diffraction or cryo-electron microscopy are available. However, the structure of the full-length antibody is still missing as the inherent protein flexibility hampers the formation of well-diffracting crystals and the reconstruction of 3D microscope images. The global structure of rituximab from its dilute solution is here elucidated by small-angle X-ray scattering (SAXS). The limited data resolution achievable by this technique has been compensated by intensive computational modelling that led to develop a new and effective procedure to characterize the average mAb conformation as well as that of the single domains. SAXS data indicated that rituximab adopts an asymmetric average conformation in solution, with a radius of gyration and a maximum linear dimension of 52 Å and 197 Å, respectively. The asymmetry is mainly due to an uneven arrangement of the two Fab units with respect to the central stem (the Fc domain) and reflects in a different conformation of the individual units. As a result, the Fab elbow angle, which is a crucial determinant for antigen recognition and binding, was found to be larger (169°) in the more distant Fab unit than that in the less distant one (143°). The whole flexibility of the antibody has been found to strongly depend on the relative inter-domain orientations, with one of the Fab arms playing a major role. The average structure and the amount of flexibility has been studied in the presence of different buffers and additives, and monitored at increasing temperature, up to the complete unfolding of the antibody. Overall, the structural characterization of rituximab can help in designing next-generation anti-CD20 antibodies and finding more efficient routes for rituximab production at industrial level.

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“…Considering the rapid development of nanoscience and nanotechnology, advanced computational methods could be valuable tools for biomolecular interaction description and comprehension as well as they can extensively contribute to the understanding of MOG as a target during the demyelination process 15 . The application of computational techniques of modelling and simulation in the demyelinating disease research is in the beginning, but showed promising results in the description and characterisation of autoantigens, antigen presenting process, and T-cell activation 16,17 .…”

Section: Introductionmentioning

confidence: 99%

Antibody-mediated biorecognition of myelin oligodendrocyte glycoprotein: computational evidence of demyelination-related epitopes

Ierich

Brum

Moraes

et al. 2019

Sci Rep

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Antigen-antibody interaction is crucial in autoimmune disease pathogenesis, as multiple sclerosis and neuromyelitis optica. Given that, autoantibodies are essential biomolecules, of which the myelin oligodendrocyte glycoprotein (MOG) can figure as a target. Here we combined Molecular Dynamics (MD), Steered Molecular Dynamics (SMD), and Atomic Force Microscope (AFM) to detail MOG recognition by its specific antibody. The complex model consisted of the MOG external domain interacting with an experimental anti-MOG antibody from the Protein Data Bank (1PKQ). Computational data demonstrated thirteen MOG residues with a robust contribution to the antigen-antibody interaction. Comprising five of the thirteen anchor residues (ASP102, HIS103, SER104, TYR105, and GLN106), the well-known MOG92–106 peptide in complex with the anti-MOG was analysed by AFM and SMD. These analyses evidenced similar force values of 780 pN and 765 pN for computational and experimental MOG92–106 and anti-MOG detachment, respectively. MOG92–106 was responsible for 75% of the total force measured between MOG external domain and anti-MOG, holding the interaction with the antibody. The antigen-antibody binding was confirmed by Surface Plasmon Resonance (SPR) measurements. Combined approaches presented here can conveniently be adjusted to detail novel molecules in diseases research. This can optimize pre-clinical steps, guiding experiments, reducing costs, and animal model usage.

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

Cited by 10 publications

References 50 publications

Genome Sequence of the Freshwater Yangtze Finless Porpoise

Genome Sequence of the Freshwater Yangtze Finless Porpoise

Structural Characterization of the Full-Length Anti-CD20 Antibody Rituximab

Antibody-mediated biorecognition of myelin oligodendrocyte glycoprotein: computational evidence of demyelination-related epitopes

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