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Investigations of the binding of [Pt2(DTBPA)Cl2](II) and [Pt2(TPXA)Cl2](II) to DNA via various cross-linking modes.

Yue H, Yang B, Wang Y, Chen G - Int J Mol Sci (2013)

Bottom Line: We have constructed models for a series of platinum-DNA adducts that represent the binding of two agents, [Pt2(DTBPA)Cl2](II) and [Pt2(TPXA)Cl2](II), to DNA via inter- and intra-strand cross-linking, and carried out molecular dynamics simulations and DNA conformational dynamics calculations.However, the effects of trans/cis-configurations of the platinum-centers on the DNA conformational distortions in the platinum-DNA adducts depend on the inter- and intra-strand cross-linking modes.In addition, we discuss the relevance of DNA base motions, including opening, shift and roll, to the changes in the parameters of the DNA major and minor grooves caused by binding of the platinum agent.

View Article: PubMed Central - PubMed

Affiliation: College of Chemistry, Beijing Normal University, Beijing 100875, China. wangy@bnu.edu.cn.

ABSTRACT
We have constructed models for a series of platinum-DNA adducts that represent the binding of two agents, [Pt2(DTBPA)Cl2](II) and [Pt2(TPXA)Cl2](II), to DNA via inter- and intra-strand cross-linking, and carried out molecular dynamics simulations and DNA conformational dynamics calculations. The effects of trans- and cis-configurations of the centers of these di-nuclear platinum agents, and of different bridging linkers, have been investigated on the conformational distortions of platinum-DNA adducts formed via inter- and intra-strand cross-links. The results demonstrate that the DNA conformational distortions for the various platinum-DNA adducts with differing cross-linking modes are greatly influenced by the difference between the platinum-platinum distance for the platinum agent and the platinum-bound N7-N7 distance for the DNA molecule, and by the flexibility of the bridging linkers in the platinum agent. However, the effects of trans/cis-configurations of the platinum-centers on the DNA conformational distortions in the platinum-DNA adducts depend on the inter- and intra-strand cross-linking modes. In addition, we discuss the relevance of DNA base motions, including opening, shift and roll, to the changes in the parameters of the DNA major and minor grooves caused by binding of the platinum agent.

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Conformational stability free energy (kcal·mol−1) and integrated distributions for (a) 4.7DTBPA-DNA (red); (b) 6.28DTBPA-DNA (blue), (c) 4.7TPXA-DNA (magenta) and (d) 6.28TPXA-DNA (green).
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f10-ijms-14-19556: Conformational stability free energy (kcal·mol−1) and integrated distributions for (a) 4.7DTBPA-DNA (red); (b) 6.28DTBPA-DNA (blue), (c) 4.7TPXA-DNA (magenta) and (d) 6.28TPXA-DNA (green).

Mentions: The 12 platinum-DNA adduct models (six [Pt2(DTBPA)Cl2](II)+DNA adducts: 26.28DTBPA-DNA, 4.7DTBPA-DNA, 3.7DTBPA-DNA, 7.28DTBPA-DNA, 6.28DTBPA-DNA and 7.26DTBPA-DNA; and six [Pt2(TPXA)Cl2](II) + DNA adducts: 26.28TPXA-DNA, 4.7TPXA-DNA, 3.7TPXA-DNA, 7.28TPXA-DNA, 6.28TPXA-DNA and 7.26TPXA-DNA) were studied by performing 50-ns unrestrained molecular dynamics simulations. The root-mean-square deviation (RMSD) values for all the backbone atoms, referenced to the corresponding starting structures, over 12 trajectories for the various intra-/inter-strand cross-linking models of the platinum-DNA adduct, were examined to determine if each system had attained equilibrium. A small RMSD value for a simulation is often considered to indicate that the system is in a stable state, whereas large RMSD values suggest the occurrence of large conformational changes. Plots of the RMSDs of the 12 platinum-DNA system simulations over time are shown in Figure 1. The calculated conformational free energies of the platinum-DNA systems as a function of time, during the last 10 ns of the simulation, were analyzed [5,37]. The corresponding results for the 4.7DTBPXA-DNA, 6.28DTBPA-DNA, 4.7TPXA-DNA and 6.28TPXA-DNA models are shown in Figure A1 (a, b, c and d, respectively). It may be seen from Figures 1 and A1 that the platinum-DNA adduct systems reached equilibrium after 10 ns, and that their energies were found to be stable during the remainder of each simulation. Therefore, the trajectory analysis for the 12 systems extracted the equilibrated conformations between 10 ns and 50 ns of the simulation time, recording 20,000 snapshots at 2-ps time intervals for each trajectory. The analyses of the hydrogen bonds of the DNA base pairs and the DNA-groove parameters around the binding sites of the DNA were performed using the time-averaged structures for these models, and are shown in Table 1, Figures 2 and 3.


Investigations of the binding of [Pt2(DTBPA)Cl2](II) and [Pt2(TPXA)Cl2](II) to DNA via various cross-linking modes.

Yue H, Yang B, Wang Y, Chen G - Int J Mol Sci (2013)

Conformational stability free energy (kcal·mol−1) and integrated distributions for (a) 4.7DTBPA-DNA (red); (b) 6.28DTBPA-DNA (blue), (c) 4.7TPXA-DNA (magenta) and (d) 6.28TPXA-DNA (green).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3821573&req=5

f10-ijms-14-19556: Conformational stability free energy (kcal·mol−1) and integrated distributions for (a) 4.7DTBPA-DNA (red); (b) 6.28DTBPA-DNA (blue), (c) 4.7TPXA-DNA (magenta) and (d) 6.28TPXA-DNA (green).
Mentions: The 12 platinum-DNA adduct models (six [Pt2(DTBPA)Cl2](II)+DNA adducts: 26.28DTBPA-DNA, 4.7DTBPA-DNA, 3.7DTBPA-DNA, 7.28DTBPA-DNA, 6.28DTBPA-DNA and 7.26DTBPA-DNA; and six [Pt2(TPXA)Cl2](II) + DNA adducts: 26.28TPXA-DNA, 4.7TPXA-DNA, 3.7TPXA-DNA, 7.28TPXA-DNA, 6.28TPXA-DNA and 7.26TPXA-DNA) were studied by performing 50-ns unrestrained molecular dynamics simulations. The root-mean-square deviation (RMSD) values for all the backbone atoms, referenced to the corresponding starting structures, over 12 trajectories for the various intra-/inter-strand cross-linking models of the platinum-DNA adduct, were examined to determine if each system had attained equilibrium. A small RMSD value for a simulation is often considered to indicate that the system is in a stable state, whereas large RMSD values suggest the occurrence of large conformational changes. Plots of the RMSDs of the 12 platinum-DNA system simulations over time are shown in Figure 1. The calculated conformational free energies of the platinum-DNA systems as a function of time, during the last 10 ns of the simulation, were analyzed [5,37]. The corresponding results for the 4.7DTBPXA-DNA, 6.28DTBPA-DNA, 4.7TPXA-DNA and 6.28TPXA-DNA models are shown in Figure A1 (a, b, c and d, respectively). It may be seen from Figures 1 and A1 that the platinum-DNA adduct systems reached equilibrium after 10 ns, and that their energies were found to be stable during the remainder of each simulation. Therefore, the trajectory analysis for the 12 systems extracted the equilibrated conformations between 10 ns and 50 ns of the simulation time, recording 20,000 snapshots at 2-ps time intervals for each trajectory. The analyses of the hydrogen bonds of the DNA base pairs and the DNA-groove parameters around the binding sites of the DNA were performed using the time-averaged structures for these models, and are shown in Table 1, Figures 2 and 3.

Bottom Line: We have constructed models for a series of platinum-DNA adducts that represent the binding of two agents, [Pt2(DTBPA)Cl2](II) and [Pt2(TPXA)Cl2](II), to DNA via inter- and intra-strand cross-linking, and carried out molecular dynamics simulations and DNA conformational dynamics calculations.However, the effects of trans/cis-configurations of the platinum-centers on the DNA conformational distortions in the platinum-DNA adducts depend on the inter- and intra-strand cross-linking modes.In addition, we discuss the relevance of DNA base motions, including opening, shift and roll, to the changes in the parameters of the DNA major and minor grooves caused by binding of the platinum agent.

View Article: PubMed Central - PubMed

Affiliation: College of Chemistry, Beijing Normal University, Beijing 100875, China. wangy@bnu.edu.cn.

ABSTRACT
We have constructed models for a series of platinum-DNA adducts that represent the binding of two agents, [Pt2(DTBPA)Cl2](II) and [Pt2(TPXA)Cl2](II), to DNA via inter- and intra-strand cross-linking, and carried out molecular dynamics simulations and DNA conformational dynamics calculations. The effects of trans- and cis-configurations of the centers of these di-nuclear platinum agents, and of different bridging linkers, have been investigated on the conformational distortions of platinum-DNA adducts formed via inter- and intra-strand cross-links. The results demonstrate that the DNA conformational distortions for the various platinum-DNA adducts with differing cross-linking modes are greatly influenced by the difference between the platinum-platinum distance for the platinum agent and the platinum-bound N7-N7 distance for the DNA molecule, and by the flexibility of the bridging linkers in the platinum agent. However, the effects of trans/cis-configurations of the platinum-centers on the DNA conformational distortions in the platinum-DNA adducts depend on the inter- and intra-strand cross-linking modes. In addition, we discuss the relevance of DNA base motions, including opening, shift and roll, to the changes in the parameters of the DNA major and minor grooves caused by binding of the platinum agent.

Show MeSH
Related in: MedlinePlus