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Atomistic Molecular Dynamics Simulations of Mitochondrial DNA Polymerase γ: Novel Mechanisms of Function and Pathogenesis

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Atomistic Molecular Dynamics Simulations of Mitochondrial DNA Polymerase γ : Novel Mechanisms of Function and Pathogenesis. / Euro, Liliya; Haapanen, Outi; Róg, Tomasz; Vattulainen, Ilpo; Suomalainen, Anu; Sharma, Vivek.

In: Biochemistry, Vol. 56, No. 9, 07.03.2017, p. 1227-1238.

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Euro, Liliya ; Haapanen, Outi ; Róg, Tomasz ; Vattulainen, Ilpo ; Suomalainen, Anu ; Sharma, Vivek. / Atomistic Molecular Dynamics Simulations of Mitochondrial DNA Polymerase γ : Novel Mechanisms of Function and Pathogenesis. In: Biochemistry. 2017 ; Vol. 56, No. 9. pp. 1227-1238.

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@article{acd0b005e7cd4a5caf065700175a95cc,
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.",
author = "Liliya Euro and Outi Haapanen and Tomasz R{\'o}g and Ilpo Vattulainen and Anu Suomalainen and Vivek Sharma",
year = "2017",
month = "3",
day = "7",
doi = "10.1021/acs.biochem.6b00934",
language = "English",
volume = "56",
pages = "1227--1238",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "9",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Atomistic Molecular Dynamics Simulations of Mitochondrial DNA Polymerase γ

T2 - Novel Mechanisms of Function and Pathogenesis

AU - Euro, Liliya

AU - Haapanen, Outi

AU - Róg, Tomasz

AU - Vattulainen, Ilpo

AU - Suomalainen, Anu

AU - Sharma, Vivek

PY - 2017/3/7

Y1 - 2017/3/7

N2 - 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.

AB - 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.

U2 - 10.1021/acs.biochem.6b00934

DO - 10.1021/acs.biochem.6b00934

M3 - Article

VL - 56

SP - 1227

EP - 1238

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 9

ER -