Atomistic Molecular Dynamics Simulations of Mitochondrial DNA Polymerase γ: Novel Mechanisms of Function and
Liliya Euro1, Outi Haapanen2, Tomasz Róg2,3
1Research Programs Unit, Molecular Neurology, University of Helsinki , 00290 Helsinki, Finland.
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.
Insights
DNA polymerase γ (Pol γ) is crucial for mitochondrial DNA replication and neurological health. Simulations reveal how DNA binding alters Pol γ structure, suggesting non-catalytic mutations may cause neurodegenerative disorders by disrupting replisome interactions.
Area of Science:
- Biochemistry
- Molecular Biology
- Neurogenetics
Background:
- DNA polymerase γ (Pol γ) is essential for mitochondrial DNA replication and its dysfunction causes neurological diseases.
- Existing crystal structures do not fully explain Pol γ's mechanism, including its activity switching, replisome interactions, or effects of non-catalytic mutations.
Purpose of the Study:
- To investigate the molecular mechanism of human Pol γ's replicative complex using atomistic classical molecular dynamics simulations.
- To elucidate the structural changes upon DNA binding and identify potential sites for replisomal interactions.
Main Methods:
- Atomistic classical molecular dynamics simulations of the human Pol γ replicative complex.
- Analysis of structural dynamics and protein-DNA interactions.
Main Results:
- DNA binding induces significant structural changes in Pol γ, including completion of the DNA-binding channel and stabilization by the accessory subunit.
- A transient replisome-binding platform is identified in the intrinsic processivity subdomain.
- Non-catalytic mutations may impair Pol γ function by disrupting these replisomal interactions.
Conclusions:
- Molecular dynamics simulations provide new insights into human Pol γ's mechanism and structural dynamics.
- Non-catalytic mutations affecting replisome interactions are a potential cause of Pol γ-associated neurodegenerative disorders.
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