Akberova N I, Zhmurov A A, Nevzorova T A, Litvinov R I
Institute of Fundamental Medicine and Biology of Kazan Federal University, Kazan, 420008, Russia.
Moscow Institute of Physics and Technology, Dolgoprudnyi, Moscow oblast, 141700, Russia.
Mol Biol (Mosk). 2016 May-Jun;50(3):509-19. doi: 10.7868/S0026898416020026.
Antibodies to DNA play an important role in the pathogenesis of autoimmune diseases. The elucidation of structural mechanisms of both the antigen recognition and the interaction of anti-DNA antibodies with DNA will help to understand the role of DNA-containing immune complexes in various pathologies and can provide a basis for new treatment modalities. Moreover, the DNA-antibody complex is an analog of specific intracellular DNA-protein interactions. In this work, we used in silico molecular dynamic simulations of bimolecular complexes of the dsDNA segment containing the Fab fragment of an anti-DNA antibody to obtain the detailed thermodynamic and structural characteristics of dynamic intermolecular interactions. Using computationally modified crystal structure of the Fab-DNA complex (PDB ID: 3VW3), we studied the equilibrium molecular dynamics of the 64M-5 antibody Fab fragment associated with the dsDNA fragment containing the thymine dimer, the product of DNA photodamage. Amino acid residues that constitute paratopes and the complementary nucleotide epitopes for the Fab-DNA construct were identified. Stacking and electrostatic interactions were found to play the main role in mediating the most specific antibody-dsDNA contacts, while hydrogen bonds were less significant. These findings may shed light on the formation and properties of pathogenic anti-DNA antibodies in autoimmune diseases, such as systemic lupus erythematosus associated with skin photosensitivity and DNA photodamage.
抗DNA抗体在自身免疫性疾病的发病机制中起着重要作用。阐明抗原识别以及抗DNA抗体与DNA相互作用的结构机制，将有助于理解含DNA免疫复合物在各种病理过程中的作用，并可为新的治疗方式提供依据。此外，DNA-抗体复合物是特定细胞内DNA-蛋白质相互作用的类似物。在这项工作中，我们对包含抗DNA抗体Fab片段的dsDNA片段的双分子复合物进行了计算机模拟分子动力学研究，以获得动态分子间相互作用的详细热力学和结构特征。利用Fab-DNA复合物的计算修饰晶体结构（PDB ID：3VW3），我们研究了与含有胸腺嘧啶二聚体（DNA光损伤产物）的dsDNA片段相关的64M-5抗体Fab片段的平衡分子动力学。确定了构成Fab-DNA构建体互补位和互补核苷酸表位的氨基酸残基。发现堆积和静电相互作用在介导最特异性的抗体-dsDNA接触中起主要作用，而氢键的作用较小。这些发现可能有助于揭示自身免疫性疾病（如与皮肤光敏性和DNA光损伤相关的系统性红斑狼疮）中致病性抗DNA抗体的形成和特性。
