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    Home > Biochemistry News > Biotechnology News > Shanghai Jiaotong University Zhao Yilei's team found that a novel sulfur bond of sulfur-modified DNA has special significance in iodine cleavage reaction and SBD protein recognition

    Shanghai Jiaotong University Zhao Yilei's team found that a novel sulfur bond of sulfur-modified DNA has special significance in iodine cleavage reaction and SBD protein recognition

    • Last Update: 2022-05-18
    • Source: Internet
    • Author: User
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    Recently, the comprehensive authoritative magazine "Proceedings of the National Academy of Sciences of the United States of America" ​​and the professional journal of physical chemistry "Physical Chemistry Chemical Physics" published the professor of Shanghai Jiaotong University School of Life Science and Technology and State Key Laboratory of Microbial Metabolism.
    The latest progress of Zhao Yilei's research team in the study of sulfur-modified DNA, respectively titled "Origin of iodine preferential attack at sulfur in phosphorothioate and subsequent PO or PS bond dissociation" (PNAS, 2022, 119(17):e2119032119), "Molecular recognition between bacterial phosphorothioate DNA and sulfur-binding domain (SBD): competition between the water cage and chalcogen-hydrophobic packet" (PCCP, 2022, 24: 9176 - 9187), two papers on "sulfur-iodine" strong halogen bonds in sulfur-modified DNA and The research results of the "sulfur-nitrogen Pro" weak sulfur bond

    .
    PNAS work elucidated that the super-strong "sulfur-iodine" halogen bond between the phosphorothioate modification site and the iodine molecule triggers a series of chemical reactions, resulting in DNA backbone cleavage or sulfur-oxygen conversion at the sulfur modification site, revealing that Molecular mechanism of highly selective splicing of sulfur-modified sites in deep sequencing by iodine cleavage

    .
    The PCCP work clarifies that the sulfur-binding protein SBD utilizes the special electronic structure of the non-hydrogen-bonded backbone nitrogen of proline to efficiently distinguish normal DNA from sulfur-modified DNA, and proposes a "sulfur bond-hydrophobic" cooperative push-pull molecular recognition mechanism

    .

    In the PNAS paper, Dr.
    Huang Qiang, Ph.
    D.
    student Li Jiayi from the School of Life Science and Technology of Shanghai Jiaotong University, and Dr.
    Gina Young Lee from the University of California, Los Angeles are the co-first authors.
    In the PCCP paper, doctoral student Li Jiayi is the first author, and co-corresponding author Dr.
    Liu Guang is responsible for the experimental verification of PT-DNA protein binding

    .
    The School of Life Science and Technology of Shanghai Jiao Tong University is the first signatory unit/corresponding unit of the two academic papers

    .

    The iodide cleavage reaction is highly sensitive to DNA phosphorothioation modification sites, and is widely used in DNA gel electrophoresis detection, deep sequencing and single-molecule sequencing of sulfur-modified bacteria
    .
    Despite its broad potential for application, the cleavage mechanism is unclear, and it has been unclear whether each phosphorothioate modification site is accurately and completely cleaved

    .
    Starting from the experimental phenomenon of iodine cleavage, the research team used high-order electron density functional theory calculations to reveal that iodine molecules chemically selectively combine with sulfur atoms in sulfur-modified DNA through super-strong "sulfur-iodine" halogen bonds, and are converted into phosphotriesters Therefore, the iodine cleavage efficiency of sulfur-modified DNA is limited by the bypass competition of sulfur-oxygen conversion

    .
    This result provides a theoretical basis for the further development of iodine-based precise deep sequencing of sulfur-modified DNA

    .

    In vivo, sulfur-modified DNA achieves special physiological functions such as epigenetic regulation and restriction modification by interacting with proteins
    .
    Although sulfur phosphorylation is widely used in antisense RNA drug development to enhance the binding affinity to plasma, cell surface and intracellular proteins, the molecular recognition mechanism of physiological DNA sulfur modification is quite different from known artificially designed nucleic acid drugs

    .
    Based on the co-crystal structure of the restriction endonuclease ScoMcrA, the authors corrected the widely circulated "sulfur hydrophobicity" drive using thermodynamic integral calculations, elucidating that the strong hydration of normal DNA and the weak hydration of sulfur-modified DNA are PT - The main driving force for DNA to enter the hydrophobic cavity of the protein, and from which a unique "sulfur-nitrogen Pro" sulfur bond weak interaction was found, which only exists in the complex of natural sulfur-modified DNA and SBD protein, and does not exist in any known complex of synthetic phosphorothioate nucleotides and drug target proteins

    .
    This noncovalent interaction is formed by electron delocalization between the σ* antibonding orbital of the PS bond and the nitrogen lone pair of the proline residue, and is characterized by the ultra-close S---N distance and linearity PS---N angle

    .
    This study provides a theoretical basis for a PT-DNA-guided gene editing molecular machine based on the SBD sulfur recognition protein

    .

    This work was funded by the National Key R&D Program, the General Program of the Natural Science Foundation of China, and the International Cooperation Joint Laboratory of Metabolism and Developmental Sciences of the Ministry of Education
    .

    Paper link:

    https:// href="https://doi.
    org/10.
    1039/D2CP00291D">https://doi.
    org/10.
    1039/D2CP00291D





    School of Life Science and Technology




    School of Life Science and Technology



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