title: A Self-Activated Mechanism for Nucleic Acid Polymerization Catalyzed by DNA/RNA Polymerases.
abstract: 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.
authors.affiliation: Laboratory of Molecular Modeling & Drug Discovery, Istituto Italiano di Tecnologia , Via Morego 30, 16163, Genoa, Italy.|IAS-5/INM-9 Computational Biomedicine and JARA-HPC, Forschungszentrum Jülich , Wilhelm-Johnen-Strasse, 52428 Jülich, Germany.
authors.forename: Vito
authors.initials: V
authors.lastname: Genna
authors.affiliation: IAS-5/INM-9 Computational Biomedicine and JARA-HPC, Forschungszentrum Jülich , Wilhelm-Johnen-Strasse, 52428 Jülich, Germany.
authors.forename: Pietro
authors.initials: P
authors.lastname: Vidossich
authors.affiliation: IAS-5/INM-9 Computational Biomedicine and JARA-HPC, Forschungszentrum Jülich , Wilhelm-Johnen-Strasse, 52428 Jülich, Germany.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Ippoliti
authors.affiliation: IAS-5/INM-9 Computational Biomedicine and JARA-HPC, Forschungszentrum Jülich , Wilhelm-Johnen-Strasse, 52428 Jülich, Germany.
authors.forename: Paolo
authors.initials: P
authors.lastname: Carloni
authors.affiliation: Laboratory of Molecular Modeling & Drug Discovery, Istituto Italiano di Tecnologia , Via Morego 30, 16163, Genoa, Italy.|IAS-5/INM-9 Computational Biomedicine and JARA-HPC, Forschungszentrum Jülich , Wilhelm-Johnen-Strasse, 52428 Jülich, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: De Vivo
mesh_terms: D002384:Catalysis; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry* / Q000187:drug effects; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism* / Q000494:pharmacology; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D008954:Models, Biological; D058105:Polymerization; D012313:RNA / Q000737:chemistry* / Q000187:drug effects; D013816:Thermodynamics
chemical_list: D012313:RNA; D004247:DNA; D012321:DNA-Directed RNA Polymerases; D004259:DNA-Directed DNA Polymerase