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A Self-Activated Mechanism for Nucleic Acid Polymerization Catalyzed by DNA/RNA Polymerases

By Vito Genna (3093072), Pietro Vidossich (1275279), Emiliano Ippoliti (628658), Paolo Carloni (128984) and Marco De Vivo (180746)


The enzymatic polymerization of DNA and RNA is the basis for genetic inheritance for all living organisms. It is catalyzed by the DNA/RNA polymerase (Pol) superfamily. Here, bioinformatics analysis reveals that the incoming nucleotide substrate always forms an H-bond between its 3′-OH and β-phosphate moieties upon formation of the Michaelis complex. This previously unrecognized H-bond implies a novel self-activated mechanism (SAM), which synergistically connects the in situ nucleophile formation with subsequent nucleotide addition and, importantly, nucleic acid translocation. Thus, SAM allows an elegant and efficient closed-loop sequence of chemical and physical steps for Pol catalysis. This is markedly different from previous mechanistic hypotheses. Our proposed mechanism is corroborated via ab initio QM/MM simulations on a specific Pol, the human DNA polymerase-η, an enzyme involved in repairing damaged DNA. The structural conservation of DNA and RNA Pols supports the possible extension of SAM to Pol enzymes from the three domains of life

Topics: Biophysics, Biochemistry, Microbiology, Cell Biology, Genetics, Molecular Biology, Developmental Biology, Virology, Environmental Sciences not elsewhere classified, Astronomical and Space Sciences not elsewhere classified, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, Physical Sciences not elsewhere classified, Self-Activated Mechanism, Polymerization Catalyzed, bioinformatics analysis, β- phosphate moieties, novel self-activated mechanism, Pol enzymes, SAM, nucleophile formation, QM, acid translocation, RNA Pols, DNA, Pol catalysis, closed-loop sequence, OH, nucleotide substrate, nucleotide addition
Year: 2016
DOI identifier: 10.1021/jacs.6b05475.s001
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