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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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Space-filling DNA models of polyamide + [Cu(BPA)OOH]+ ligand binding to the minor groove of DNA; (A) for hairpin polyamide + [Cu(BPA)OOH]+-d(AATATCCACCTGCA)2 (HPD-BPA); (B) for cyclic polyamide + [Cu(BPA)OOH]+ -d(CGCTAACAGGC)2 (CPDγ-BPA); (C) average structure of hairpin polyamide + [Cu(BPA)OOH]+ ligand orientating to C4'H atom of sugar.
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Figure 2: Space-filling DNA models of polyamide + [Cu(BPA)OOH]+ ligand binding to the minor groove of DNA; (A) for hairpin polyamide + [Cu(BPA)OOH]+-d(AATATCCACCTGCA)2 (HPD-BPA); (B) for cyclic polyamide + [Cu(BPA)OOH]+ -d(CGCTAACAGGC)2 (CPDγ-BPA); (C) average structure of hairpin polyamide + [Cu(BPA)OOH]+ ligand orientating to C4'H atom of sugar.

Mentions: Analyses of the average structures of the trajectories obtained from the simulations of HPD-BPA and CPDγ-BPA reveal spatial details of the interactions of the entire ligands with DNA molecules, which supports the general observations described above. Specifically, (1) for HPD-BPA, the cleavage agent of [Cu(BPA) OOH]+ is located at the minor grove of DNA during the course of the simulation; the equatorial plane of the [Cu(BPA)]2+ nuclease is parallel to the wall of the minor groove of DNA with the angle of 12° between the plane of nuclease and the wall of minor groove, as shown in Figure 2A. However, for CPDγ-BPA, the cleavage agent of [Cu(BPA) OOH]+ cannot remain in the minor groove, whose orientation is removed from the minor groove of DNA, resulting from the rigidity of the N-tail of cyclic polyamide that constrains the flexibility of the [Cu(BPA)]2+ nuclease, as shown in Figure 2B. (2) The chains of polyamide for each system also remain almost parallel to the wall of the minor groove of DNA; the N-H groups nearby Im/Py of polyamides play an important role in acting as H-bonds donors to the N or O atoms of nucleobases located on the floor of the minor groove of DNA. Moreover, the H atom of the branch C atom in [Cu(BPA)]2+ and the N or O atom of bases of neighboring DNA can also form H-bonds. The affinity of polyamides with DNA are enhanced mainly by an increase in the number and strength of observed H-bonds between the polyamide-nuclease ligand and the DNA molecule, i.e., the H-bonds formed between the C-H groups of [Cu(BPA)]2+ and O4 atom of T8 base in DNA with C-O distance of about 3.1 Å. (3) The average structure of each system presents a relatively stable spatial conformation during the course of simulation. Figures 2A and 2B show the average structures from the simulations for HPD-BPA and CPDγ-BPA, respectively. The average structure with the average Od-C4'H distance of 2.78 Å for HPD-BPA in Figure 2C predicts the DNA cleavage possibility at the tail region of the polyamide, because that the Cu atom of [Cu(BPA)]2+ approaches the nearest sugar C4'H of C10 base. However, from Figure 2B for CPDγ-BPA, it is obvious that the structural characteristics reveal theoretically the poor cleavage ability of [Cu(BPA)]2+ nuclease due to the restraint of the rigid linker of the cyclic polyamide bound to the [Cu(BPA)]2+ nuclease. Namely, the restraint of DNA cleavage of the [Cu(BPA)]2+ nuclease results from the short linker between the branch C atom of nuclease and backbone of cyclic polyamide.


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)

Space-filling DNA models of polyamide + [Cu(BPA)OOH]+ ligand binding to the minor groove of DNA; (A) for hairpin polyamide + [Cu(BPA)OOH]+-d(AATATCCACCTGCA)2 (HPD-BPA); (B) for cyclic polyamide + [Cu(BPA)OOH]+ -d(CGCTAACAGGC)2 (CPDγ-BPA); (C) average structure of hairpin polyamide + [Cu(BPA)OOH]+ ligand orientating to C4'H atom of sugar.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 2: Space-filling DNA models of polyamide + [Cu(BPA)OOH]+ ligand binding to the minor groove of DNA; (A) for hairpin polyamide + [Cu(BPA)OOH]+-d(AATATCCACCTGCA)2 (HPD-BPA); (B) for cyclic polyamide + [Cu(BPA)OOH]+ -d(CGCTAACAGGC)2 (CPDγ-BPA); (C) average structure of hairpin polyamide + [Cu(BPA)OOH]+ ligand orientating to C4'H atom of sugar.
Mentions: Analyses of the average structures of the trajectories obtained from the simulations of HPD-BPA and CPDγ-BPA reveal spatial details of the interactions of the entire ligands with DNA molecules, which supports the general observations described above. Specifically, (1) for HPD-BPA, the cleavage agent of [Cu(BPA) OOH]+ is located at the minor grove of DNA during the course of the simulation; the equatorial plane of the [Cu(BPA)]2+ nuclease is parallel to the wall of the minor groove of DNA with the angle of 12° between the plane of nuclease and the wall of minor groove, as shown in Figure 2A. However, for CPDγ-BPA, the cleavage agent of [Cu(BPA) OOH]+ cannot remain in the minor groove, whose orientation is removed from the minor groove of DNA, resulting from the rigidity of the N-tail of cyclic polyamide that constrains the flexibility of the [Cu(BPA)]2+ nuclease, as shown in Figure 2B. (2) The chains of polyamide for each system also remain almost parallel to the wall of the minor groove of DNA; the N-H groups nearby Im/Py of polyamides play an important role in acting as H-bonds donors to the N or O atoms of nucleobases located on the floor of the minor groove of DNA. Moreover, the H atom of the branch C atom in [Cu(BPA)]2+ and the N or O atom of bases of neighboring DNA can also form H-bonds. The affinity of polyamides with DNA are enhanced mainly by an increase in the number and strength of observed H-bonds between the polyamide-nuclease ligand and the DNA molecule, i.e., the H-bonds formed between the C-H groups of [Cu(BPA)]2+ and O4 atom of T8 base in DNA with C-O distance of about 3.1 Å. (3) The average structure of each system presents a relatively stable spatial conformation during the course of simulation. Figures 2A and 2B show the average structures from the simulations for HPD-BPA and CPDγ-BPA, respectively. The average structure with the average Od-C4'H distance of 2.78 Å for HPD-BPA in Figure 2C predicts the DNA cleavage possibility at the tail region of the polyamide, because that the Cu atom of [Cu(BPA)]2+ approaches the nearest sugar C4'H of C10 base. However, from Figure 2B for CPDγ-BPA, it is obvious that the structural characteristics reveal theoretically the poor cleavage ability of [Cu(BPA)]2+ nuclease due to the restraint of the rigid linker of the cyclic polyamide bound to the [Cu(BPA)]2+ nuclease. Namely, the restraint of DNA cleavage of the [Cu(BPA)]2+ nuclease results from the short linker between the branch C atom of nuclease and backbone of cyclic polyamide.

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