title: An anti-DNA antibody prefers damaged dsDNA over native.
abstract: DNA-protein interactions, including DNA-antibody complexes, have both fundamental and practical significance. In particular, antibodies against double-stranded DNA play an important role in the pathogenesis of autoimmune diseases. Elucidation of structural mechanisms of an antigen recognition and interaction of anti-DNA antibodies provides a basis for understanding the role of DNA-containing immune complexes in human pathologies and for new treatments. Here we used Molecular Dynamic simulations of bimolecular complexes of a segment of dsDNA with a monoclonal anti-DNA antibody's Fab-fragment to obtain detailed structural and physical characteristics of the dynamic intermolecular interactions. Using a computationally modified crystal structure of a Fab-DNA complex (PDB: 3VW3), we studied in silico equilibrium Molecular Dynamics of the Fab-fragment associated with two homologous dsDNA fragments, containing or not containing dimerized thymine, a product of DNA photodamage. The Fab-fragment interactions with the thymine dimer-containing DNA was thermodynamically more stable than with the native DNA. The amino acid residues constituting a paratope and the complementary nucleotide epitopes for both Fab-DNA constructs were identified. Stacking and electrostatic interactions were shown to play the main role in the antibody-dsDNA contacts, while hydrogen bonds were less significant. The aggregate of data show that the chemically modified dsDNA (containing a covalent thymine dimer) has a higher affinity toward the antibody and forms a stronger immune complex. These findings provide a mechanistic insight into formation and properties of the pathogenic anti-DNA antibodies in autoimmune diseases, such as systemic lupus erythematosus, associated with skin photosensibilization and DNA photodamage.
authors.affiliation: a Department of Biochemistry and Biotechnology, Institute of Fundamental Medicine and Biology , Kazan Federal University , 18 Kremlyovskaya St., Kazan 420111 , Russian Federation.
authors.forename: N I
authors.initials: NI
authors.lastname: Akberova
authors.affiliation: b Moscow Institute of Physics & Technology , 9 Institutskiy Per., Dolgoprudny, Moscow Region 141700 , Russian Federation.
authors.forename: A A
authors.initials: AA
authors.lastname: Zhmurov
authors.affiliation: a Department of Biochemistry and Biotechnology, Institute of Fundamental Medicine and Biology , Kazan Federal University , 18 Kremlyovskaya St., Kazan 420111 , Russian Federation.
authors.forename: T A
authors.initials: TA
authors.lastname: Nevzorova
authors.affiliation: c Department of Cell and Developmental Biology , University of Pennsylvania Perelman School of Medicine , 1109 BRB II/III, 421 Curie Blvd., Philadelphia , PA 19104-6058 , USA.
authors.forename: R I
authors.initials: RI
authors.lastname: Litvinov
mesh_terms: D000974:Antibodies, Antinuclear / Q000737:chemistry* / Q000378:metabolism; D000936:Antigen-Antibody Complex; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D006860:Hydrogen Bonding; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D011740:Pyrimidine Dimers / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; D007140:Immunoglobulin Fab Fragments; D011740:Pyrimidine Dimers; D004247:DNA
keywords: Molecular Dynamics simulation; anti-DNA antibody; dsDNA; immune complex; thymine dimer