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Comparative Molecular Dynamics Studies of Human DNAPolymerase η

View Article: PubMed Central - PubMed

ABSTRACT

High-energyultraviolet radiation damages DNA through the formationof cyclobutane pyrimidine dimers, which stall replication. When thelesion is a thymine–thymine dimer (TTD), human DNA polymeraseη (Pol η) assists in resuming the replication processby inserting nucleotides opposite the damaged site. We performed extensivemolecular dynamics (MD) simulations to investigate the structuraland dynamical effects of four different Pol η complexes withor without a TTD and with either dATP or dGTP as the incoming base.No major differences in the overall structures and equilibrium dynamicswere detected among the four systems, suggesting that the specificityof this enzyme is due predominantly to differences in local interactionsin the binding regions. Analysis of the hydrogen-bonding interactionsbetween the enzyme and the DNA and dNTP provided molecular-level insights.Specifically, the TTD was observed to engage in more hydrogen-bondinginteractions with the enzyme than its undamaged counterpart of twonormal thymines. The resulting greater rigidity and specific orientationof the TTD are consistent with the experimental observation of higherprocessivity and overall efficiency at TTD sites than at analogoussites with two normal thymines. The similarities between the systemscontaining dATP and dGTP are consistent with the experimental observationof relatively low fidelity with respect to the incoming base. Moreover,Q38 and R61, two strictly conserved amino acids across the Pol ηfamily, were found to exhibit persistent hydrogen-bonding interactionswith the TTD and cation-π interactions with the free base, respectively.Thus, these simulations provide molecular level insights into thebasis for the selectivity and efficiency of this enzyme, as well asthe roles of the two most strictly conserved residues.

No MeSH data available.


Related in: MedlinePlus

Time evolutionof the major (black) and minor (red) groove widthsfor one of the three independent trajectories of the systems TTD3′-A(A), TTD3′-G (B), N/A-A (C), and TTD5′-A (D). The analogousdata obtained from all trajectories are provided in Figure S11.
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fig6: Time evolutionof the major (black) and minor (red) groove widthsfor one of the three independent trajectories of the systems TTD3′-A(A), TTD3′-G (B), N/A-A (C), and TTD5′-A (D). The analogousdata obtained from all trajectories are provided in Figure S11.

Mentions: The major and minor groovewidths of the DNA strands bound to Polη were also examined. The time evolution of these widths isdepicted in Figure 6 for one independent trajectory per system, and the data for alltrajectories are provided in Figure S11. As depicted in Figure 6, these parameters remained extremely steady over the entiretrajectory for systems N/A-A and TTD5′-A but exhibited widerfluctuations for systems TTD3′-A and TTD3′-G. Thesechanges suggest that the DNA may be more mobile in the TTD3′-Aand TTD3′-G systems.


Comparative Molecular Dynamics Studies of Human DNAPolymerase η
Time evolutionof the major (black) and minor (red) groove widthsfor one of the three independent trajectories of the systems TTD3′-A(A), TTD3′-G (B), N/A-A (C), and TTD5′-A (D). The analogousdata obtained from all trajectories are provided in Figure S11.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4696480&req=5

fig6: Time evolutionof the major (black) and minor (red) groove widthsfor one of the three independent trajectories of the systems TTD3′-A(A), TTD3′-G (B), N/A-A (C), and TTD5′-A (D). The analogousdata obtained from all trajectories are provided in Figure S11.
Mentions: The major and minor groovewidths of the DNA strands bound to Polη were also examined. The time evolution of these widths isdepicted in Figure 6 for one independent trajectory per system, and the data for alltrajectories are provided in Figure S11. As depicted in Figure 6, these parameters remained extremely steady over the entiretrajectory for systems N/A-A and TTD5′-A but exhibited widerfluctuations for systems TTD3′-A and TTD3′-G. Thesechanges suggest that the DNA may be more mobile in the TTD3′-Aand TTD3′-G systems.

View Article: PubMed Central - PubMed

ABSTRACT

High-energyultraviolet radiation damages DNA through the formationof cyclobutane pyrimidine dimers, which stall replication. When thelesion is a thymine–thymine dimer (TTD), human DNA polymeraseη (Pol η) assists in resuming the replication processby inserting nucleotides opposite the damaged site. We performed extensivemolecular dynamics (MD) simulations to investigate the structuraland dynamical effects of four different Pol η complexes withor without a TTD and with either dATP or dGTP as the incoming base.No major differences in the overall structures and equilibrium dynamicswere detected among the four systems, suggesting that the specificityof this enzyme is due predominantly to differences in local interactionsin the binding regions. Analysis of the hydrogen-bonding interactionsbetween the enzyme and the DNA and dNTP provided molecular-level insights.Specifically, the TTD was observed to engage in more hydrogen-bondinginteractions with the enzyme than its undamaged counterpart of twonormal thymines. The resulting greater rigidity and specific orientationof the TTD are consistent with the experimental observation of higherprocessivity and overall efficiency at TTD sites than at analogoussites with two normal thymines. The similarities between the systemscontaining dATP and dGTP are consistent with the experimental observationof relatively low fidelity with respect to the incoming base. Moreover,Q38 and R61, two strictly conserved amino acids across the Pol ηfamily, were found to exhibit persistent hydrogen-bonding interactionswith the TTD and cation-π interactions with the free base, respectively.Thus, these simulations provide molecular level insights into thebasis for the selectivity and efficiency of this enzyme, as well asthe roles of the two most strictly conserved residues.

No MeSH data available.


Related in: MedlinePlus