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Investigation and improvement of DNA cleavage models of polyamide + Cu(II) nuclease + OOH- ligands bound to DNA.

Yue H, Zhu Y, Wang Y, Chen G - BMC Struct. Biol. (2010)

Bottom Line: We carried out a series of molecular dynamics simulations for the nuclease [Cu(BPA)]2+ or [Cu(IDB)]2+ bound to the hairpin/cyclic polyamide and associated with DNA to investigate the selective DNA cleavage properties of Cu(II)-based artificial nucleases.The simulated results demonstrate that the DNA cleavage selectivity of the two nucleases assisted by the hairpin polyamide is improved efficiently.Current investigations provide an insight into the DNA cleavage specificities of chemical nucleases assisted by an appropriate nucleic acid recognition agent.

View Article: PubMed Central - HTML - PubMed

Affiliation: College of Chemistry, Beijing Normal University, Beijing100875, China.

ABSTRACT

Background: Copper nucleases as a famous class of artificial metallonucleases have attracted considerable interest in relation to their diverse potentials not only as therapeutic agents but also in genomic researches. Copper nucleases present high efficient oxidative cleavage of DNA, in which DNA strand scission occurs generally after hydrogen atom abstracted from a sugar moiety. In order to achieve the selective cleavage of DNA sequences by copper nucleases, the DNA specific recognition agents of the Dervan-type hairpin and cyclic polyamides can be considered as proper carriers of copper nucleases. Investigation of the DNA cleavage selectivity of copper nucleases assisted by the hairpin and cyclic polyamides at the molecular level has not yet been elucidated.

Results: We carried out a series of molecular dynamics simulations for the nuclease [Cu(BPA)]2+ or [Cu(IDB)]2+ bound to the hairpin/cyclic polyamide and associated with DNA to investigate the selective DNA cleavage properties of Cu(II)-based artificial nucleases. The simulated results demonstrate that the DNA cleavage selectivity of the two nucleases assisted by the hairpin polyamide is improved efficiently. The [Cu(BPA)]2+ or [Cu(IDB)]2+ nuclease with a substrate OOH- bound to the hairpin polyamide can be stably located at the minor groove of DNA, and possibly abstracts H atom from the sugar of DNA. However, the DNA cleavage properties of the two nucleases assisted by the cyclic polyamide are significantly poor due to the rigidity of linking region between the cyclic polyamide and nuclease. With introduction of the flexible linker -CH2CH2CH2NH2, the modified cyclic polyamide can assist the two copper nucleases to improve the selective DNA cleavage properties efficiently.

Conclusion: A flexible linker and a proper binding site of the polyamide-type recognition agents play an important role in improving the DNA cleavage selectivity of copper nucleases. Current investigations provide an insight into the DNA cleavage specificities of chemical nucleases assisted by an appropriate nucleic acid recognition agent.

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Related in: MedlinePlus

RMSDs with respect to the starting structures in the simulations of polyamide + [Cu(BPA)OOH]+-DNA (polyamide + [Cu(BPA)OOH]+ -DNA (black), polyamide + [Cu(BPA)OOH]+ (blue), and DNA alone (magenta)), RDF curves of the distal Od atom of OOH-C1'H atom(pink)/C4'H atom (navy) of sugars, probability distributions (the histogram bin width of 0.1 Å), and integration plot of probabilities of Od-C1'H (pink) and Od-C4'H (navy) distances: (A), (C), (E), (G) for hairpin polyamide + [Cu(BPA)OOH]+-d(AATATCCACCTGCA)2 (HPD-BPA) and (B), (D), (F) for cyclic polyamide + [Cu(BPA)OOH]+ -d(CGCTAACAGGC)2 (CPDγ-BPA).
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Figure 1: RMSDs with respect to the starting structures in the simulations of polyamide + [Cu(BPA)OOH]+-DNA (polyamide + [Cu(BPA)OOH]+ -DNA (black), polyamide + [Cu(BPA)OOH]+ (blue), and DNA alone (magenta)), RDF curves of the distal Od atom of OOH-C1'H atom(pink)/C4'H atom (navy) of sugars, probability distributions (the histogram bin width of 0.1 Å), and integration plot of probabilities of Od-C1'H (pink) and Od-C4'H (navy) distances: (A), (C), (E), (G) for hairpin polyamide + [Cu(BPA)OOH]+-d(AATATCCACCTGCA)2 (HPD-BPA) and (B), (D), (F) for cyclic polyamide + [Cu(BPA)OOH]+ -d(CGCTAACAGGC)2 (CPDγ-BPA).

Mentions: To investigate the DNA cleavage specificities of the metal nuclease assisted by different recognition agents, the [Cu(BPA)OOH]+ ligand was bound to hairpin and cyclic polyamides, respectively. The two polyamide + [Cu(BPA)OOH]+ - DNA complexes are assigned as HPD-BPA and CPDγ-BPA. The small RMSD values of these two systems predict that the interactions between the polyamide ligand and the DNA molecule in each system are strong enough to hold firmly the [Cu(BPA)OOH]+ ligand in the minor groove of DNA. Namely, the average RMSD values of two systems derived from the simulations over 12500 structures in the computed trajectories for HPD-BPA and CPDγ-BPA are respective 2.38 and 2.31 Å, as shown in Figures 1A and 1B. The mean-square fluctuations correlated with temperature factors for the systems support that each system reaches a relatively stable situation with small RMSD changes during the course of the simulation. The radial distribution functions (RDF) between the Od atom of OOH- ligand and the hydrogen atoms of sugar of DNA may supply primary information regarding DNA strand scission possibility. The RDFs, probability distributions and integration plots of probabilities of the Od-C1'H and Od-C4'H distances of the nearest cytosine and thymine bases, are shown in Figures 1C, E and 1G, respectively, for HPD-BPA. The RDFs and the probability distributions of the Od-C1'H and Od-C4'H distances of the nearest cytosine and thymine bases are shown in Figures 1D, and 1F, respectively, for CPDγ-BPA. Figures 1C and 1D show the first sharp RDF peak centered at 2.85 Å corresponding to a direct interaction of OOH- with C4'H atom for HPD-BPA, and that centered at 5.98 Å with the C4'H atom for CPDγ-BPA, respectively. In addition, Figures 1E and 1F present the probability distributions of the Od-C4'H distance less than 3.5 Å with 76.5% of the simulation time versus those of the Od-C1'H distance less than 3.5 Å with 16.5% of the simulation time for HPD-BPA, and the probability distributions of the Od-sugar hydrogen atom distances less than 3.5 Å all with 0% of simulation times for CPDγ-BPA, respectively. The integration plots of probabilities in Figure 1G show that the C4'H abstraction is more favorable than the C1'H one for HPD-BPA. However, Figure 1F presents the properties of the poor hydrogen abstractions from the sugars of DNA for CPDγ-BPA.


Investigation and improvement of DNA cleavage models of polyamide + Cu(II) nuclease + OOH- ligands bound to DNA.

Yue H, Zhu Y, Wang Y, Chen G - BMC Struct. Biol. (2010)

RMSDs with respect to the starting structures in the simulations of polyamide + [Cu(BPA)OOH]+-DNA (polyamide + [Cu(BPA)OOH]+ -DNA (black), polyamide + [Cu(BPA)OOH]+ (blue), and DNA alone (magenta)), RDF curves of the distal Od atom of OOH-C1'H atom(pink)/C4'H atom (navy) of sugars, probability distributions (the histogram bin width of 0.1 Å), and integration plot of probabilities of Od-C1'H (pink) and Od-C4'H (navy) distances: (A), (C), (E), (G) for hairpin polyamide + [Cu(BPA)OOH]+-d(AATATCCACCTGCA)2 (HPD-BPA) and (B), (D), (F) for cyclic polyamide + [Cu(BPA)OOH]+ -d(CGCTAACAGGC)2 (CPDγ-BPA).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2984560&req=5

Figure 1: RMSDs with respect to the starting structures in the simulations of polyamide + [Cu(BPA)OOH]+-DNA (polyamide + [Cu(BPA)OOH]+ -DNA (black), polyamide + [Cu(BPA)OOH]+ (blue), and DNA alone (magenta)), RDF curves of the distal Od atom of OOH-C1'H atom(pink)/C4'H atom (navy) of sugars, probability distributions (the histogram bin width of 0.1 Å), and integration plot of probabilities of Od-C1'H (pink) and Od-C4'H (navy) distances: (A), (C), (E), (G) for hairpin polyamide + [Cu(BPA)OOH]+-d(AATATCCACCTGCA)2 (HPD-BPA) and (B), (D), (F) for cyclic polyamide + [Cu(BPA)OOH]+ -d(CGCTAACAGGC)2 (CPDγ-BPA).
Mentions: To investigate the DNA cleavage specificities of the metal nuclease assisted by different recognition agents, the [Cu(BPA)OOH]+ ligand was bound to hairpin and cyclic polyamides, respectively. The two polyamide + [Cu(BPA)OOH]+ - DNA complexes are assigned as HPD-BPA and CPDγ-BPA. The small RMSD values of these two systems predict that the interactions between the polyamide ligand and the DNA molecule in each system are strong enough to hold firmly the [Cu(BPA)OOH]+ ligand in the minor groove of DNA. Namely, the average RMSD values of two systems derived from the simulations over 12500 structures in the computed trajectories for HPD-BPA and CPDγ-BPA are respective 2.38 and 2.31 Å, as shown in Figures 1A and 1B. The mean-square fluctuations correlated with temperature factors for the systems support that each system reaches a relatively stable situation with small RMSD changes during the course of the simulation. The radial distribution functions (RDF) between the Od atom of OOH- ligand and the hydrogen atoms of sugar of DNA may supply primary information regarding DNA strand scission possibility. The RDFs, probability distributions and integration plots of probabilities of the Od-C1'H and Od-C4'H distances of the nearest cytosine and thymine bases, are shown in Figures 1C, E and 1G, respectively, for HPD-BPA. The RDFs and the probability distributions of the Od-C1'H and Od-C4'H distances of the nearest cytosine and thymine bases are shown in Figures 1D, and 1F, respectively, for CPDγ-BPA. Figures 1C and 1D show the first sharp RDF peak centered at 2.85 Å corresponding to a direct interaction of OOH- with C4'H atom for HPD-BPA, and that centered at 5.98 Å with the C4'H atom for CPDγ-BPA, respectively. In addition, Figures 1E and 1F present the probability distributions of the Od-C4'H distance less than 3.5 Å with 76.5% of the simulation time versus those of the Od-C1'H distance less than 3.5 Å with 16.5% of the simulation time for HPD-BPA, and the probability distributions of the Od-sugar hydrogen atom distances less than 3.5 Å all with 0% of simulation times for CPDγ-BPA, respectively. The integration plots of probabilities in Figure 1G show that the C4'H abstraction is more favorable than the C1'H one for HPD-BPA. However, Figure 1F presents the properties of the poor hydrogen abstractions from the sugars of DNA for CPDγ-BPA.

Bottom Line: We carried out a series of molecular dynamics simulations for the nuclease [Cu(BPA)]2+ or [Cu(IDB)]2+ bound to the hairpin/cyclic polyamide and associated with DNA to investigate the selective DNA cleavage properties of Cu(II)-based artificial nucleases.The simulated results demonstrate that the DNA cleavage selectivity of the two nucleases assisted by the hairpin polyamide is improved efficiently.Current investigations provide an insight into the DNA cleavage specificities of chemical nucleases assisted by an appropriate nucleic acid recognition agent.

View Article: PubMed Central - HTML - PubMed

Affiliation: College of Chemistry, Beijing Normal University, Beijing100875, China.

ABSTRACT

Background: Copper nucleases as a famous class of artificial metallonucleases have attracted considerable interest in relation to their diverse potentials not only as therapeutic agents but also in genomic researches. Copper nucleases present high efficient oxidative cleavage of DNA, in which DNA strand scission occurs generally after hydrogen atom abstracted from a sugar moiety. In order to achieve the selective cleavage of DNA sequences by copper nucleases, the DNA specific recognition agents of the Dervan-type hairpin and cyclic polyamides can be considered as proper carriers of copper nucleases. Investigation of the DNA cleavage selectivity of copper nucleases assisted by the hairpin and cyclic polyamides at the molecular level has not yet been elucidated.

Results: We carried out a series of molecular dynamics simulations for the nuclease [Cu(BPA)]2+ or [Cu(IDB)]2+ bound to the hairpin/cyclic polyamide and associated with DNA to investigate the selective DNA cleavage properties of Cu(II)-based artificial nucleases. The simulated results demonstrate that the DNA cleavage selectivity of the two nucleases assisted by the hairpin polyamide is improved efficiently. The [Cu(BPA)]2+ or [Cu(IDB)]2+ nuclease with a substrate OOH- bound to the hairpin polyamide can be stably located at the minor groove of DNA, and possibly abstracts H atom from the sugar of DNA. However, the DNA cleavage properties of the two nucleases assisted by the cyclic polyamide are significantly poor due to the rigidity of linking region between the cyclic polyamide and nuclease. With introduction of the flexible linker -CH2CH2CH2NH2, the modified cyclic polyamide can assist the two copper nucleases to improve the selective DNA cleavage properties efficiently.

Conclusion: A flexible linker and a proper binding site of the polyamide-type recognition agents play an important role in improving the DNA cleavage selectivity of copper nucleases. Current investigations provide an insight into the DNA cleavage specificities of chemical nucleases assisted by an appropriate nucleic acid recognition agent.

Show MeSH
Related in: MedlinePlus