title: Atomistic Molecular Dynamics Simulations of Mitochondrial DNA Polymerase γ: Novel Mechanisms of Function and Pathogenesis.
abstract: DNA polymerase γ (Pol γ) is a key component of the mitochondrial DNA replisome and an important cause of neurological diseases. Despite the availability of its crystal structures, the molecular mechanism of DNA replication, the switch between polymerase and exonuclease activities, the site of replisomal interactions, and functional effects of patient mutations that do not affect direct catalysis have remained elusive. Here we report the first atomistic classical molecular dynamics simulations of the human Pol γ replicative complex. Our simulation data show that DNA binding triggers remarkable changes in the enzyme structure, including (1) completion of the DNA-binding channel via a dynamic subdomain, which in the apo form blocks the catalytic site, (2) stabilization of the structure through the distal accessory β-subunit, and (3) formation of a putative transient replisome-binding platform in the "intrinsic processivity" subdomain of the enzyme. Our data indicate that noncatalytic mutations may disrupt replisomal interactions, thereby causing Pol γ-associated neurodegenerative disorders.
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki , 00290 Helsinki, Finland.
authors.forename: Liliya
authors.initials: L
authors.lastname: Euro
authors.affiliation: Department of Physics, Tampere University of Technology , Tampere, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Haapanen
authors.affiliation: Department of Physics, Tampere University of Technology , Tampere, Finland.|Department of Physics, University of Helsinki , Helsinki, Finland.
authors.forename: Tomasz
authors.identifier: 0000-0001-6765-7013
authors.initials: T
authors.lastname: Róg
authors.affiliation: Department of Physics, Tampere University of Technology , Tampere, Finland.|Department of Physics, University of Helsinki , Helsinki, Finland.|MEMPHYS-Center for Biomembrane Physics, University of Southern Denmark , Odense, Denmark.
authors.forename: Ilpo
authors.identifier: 0000-0001-7408-3214
authors.initials: I
authors.lastname: Vattulainen
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki , 00290 Helsinki, Finland.|Department of Neurology, Helsinki University Hospital , Helsinki, Finland.|Neuroscience Center, University of Helsinki , 00790 Helsinki, Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
authors.affiliation: Department of Physics, Tampere University of Technology , Tampere, Finland.|Department of Physics, University of Helsinki , Helsinki, Finland.|Institute of Biotechnology, University of Helsinki , Helsinki, Finland.
authors.forename: Vivek
authors.identifier: 0000-0002-8838-3151
authors.initials: V
authors.lastname: Sharma
mesh_terms: D020134:Catalytic Domain; D004247:DNA / Q000378:metabolism; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000201:enzymology*; D056004:Molecular Dynamics Simulation; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000235:genetics; D017433:Protein Structure, Secondary; D012399:Rotation
chemical_list: D004247:DNA; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase