Dna intercalators pdf

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Hence, the statistical variation in the number of dye molecules binding to the nanorail does not account for the variance in our data. Hence we conclude that the standard deviation of the twist is likely due to thermal motion. By inserting bases to the original design of the nanorail, we also simulated the twisting of the nanorail using the CanDo 35 simulation tool.

The number of predicted twists increased as the number of inserted bases increased Supporting Information S7 , suggesting that the addition of intercalator dyes increased the space between bases. Furthermore, we studied reversibility of nanorail twisting by removing the intercalator dyes. Global twisting of DNA origami nanorails can be induced by intercalators such as ethidium bromide and SYBR Green I, and the number of twists increases as the concentration of the intercalator increases in solution.

We found that reversible post-synthesis conformational changes to the DNA nanostructures is possible through utilization of intercalating agents, the degree of change is dependent on the concentration of the chemical agents and saturates at a certain concentration. The root-mean-square spread in the twist was found to be consistent with the equilibrium fluctuations expected based on the stiffness of duplex DNA. Our nanorail system provides a convenient bed with which to study mechanical distortion of DNA due to DNA binding molecules.

We suggest that the effect of the intercalator dyes on the stability of DNA nanostructures — e. Chromatin analogous gene expression CAGE 21 structures are potential models. Finally, the current study provides biology with a framework to discuss the interaction of intercalating agents with complex DNA systems at high-level organizations such as chromosomal and sub-chromosomal arrangements. All upstream experiments were conducted in a final nanorail concentration of 1. Twist of the structures were induced by addition of concentrated intercalator dye to the assembled origami solutions and left at room temperature for two hours before the application of the sample to the mica surfaces.

Non-contact tapping AFM mode was preferred mode when collecting images of the nanorails. Low tip oscillations and attractive forces reduces tip degradation, allowing for higher resolution AFM images. Collected AFM images were statistically analyzed, where generally a large number of nanorails were counted to create means and variance for each concentration examined. Zhirnov, V. Nucleic acid memory. Seeman, N. Nanomaterials Based on DNA. Rothemund, P. Folding DNA to create nanoscale shapes and patterns.

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Methods Enzymol. Hayashi, M. Direct observation of the reversible unwinding of a single DNA molecule caused by the intercalation of ethidium bromide. McGhee, J. Theoretical aspects of DNA-protein interactions: co-operative and non-co-operative binding of large ligands to a one-dimensional homogeneous lattice. Nyberg, L. Heterogeneous staining: a tool for studies of how fluorescent dyes affect the physical properties of DNA. Wilson, W. Mechanism of intercalation: ion effects on the equilibrium and kinetic constants for the interaction of propidium and ethidium with DNA.

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Biopolymers 99 , — Hammond, G. A correlation of reaction rates. Leffler, J. Parameters for the description of transition states. Hopkins, H. Enthalpy and entropy changes for the intercalation of small molecules to DNA. Substituted naphthalene monoimides and naphthalene diimides. Solution Chem. Intercalation binding of 6-substituted naphthothiopheneamides to DNA: enthalpy and entropy components. Biopolymers 31 , — Schwaller, M. Thermodynamics of drug-DNA interactions: entropy-driven intercalation and enthalpy-driven outside binding in the ellipticine series.

Analysis of cooperativity and ion effects in the interaction of quinacrine with DNA. Biopolymers 18 , — Petty, J. Thermodynamic characterization of the association of cyanine dyes with DNA. B , — Larsson, A. Mapping the phase diagram of single DNA molecule force-induced melting in the presence of ethidium.

Biebricher, A. The complexes Ru-tha, Ru-dha, and Ru-bip cause a significant red shift ca. The intercalation of porphyrins is evident from the enthalpic terms measured by ITC, which are similar to those reported for ethidium bromide with a G4 tetraplex. This flexibility makes simultaneous arene-base stacking and N7-covalent binding compatible. The tetrahydroanthracene complex Ru-tha is 10x more toxic to cancer cells than the biphenyl complex Ru-bip.

Deshielding of intercalator NMR resonances is rare. Further work12 has provided evidence that coordinative and intercalative interactions of Ru-bip can affect the base-pairing of duplex DNA. Ruthenium arene intercalation is dynamic in nature: equilibria can exist between intercalated and non- intercalated conformers, Fig.

The displacement, or flip-out, of bases near the modified sites is common for DNA modified covalently by aromatic or bulky intercalators, and may act as a trigger for nucleotide excision repair NER. Comparison with dual-mode organic intercalators Polycyclic aromatic hydrocarbons,61 heterocyclic amines,62 their nitro derivatives and food mutagens, are well known classes of environmental pollutants that cause the formation of bulky DNA lesions in vivo. Oligonucleotides containing these groups have been studied extensively.

The enhanced lesion dynamics may play an important role in facilitating NER. Interactions between dual function transition metal complexes and DNA show some similarities to those of covalent polycyclic aromatic carcinogen-DNA adducts,61 especially to the N7-alkylating- intercalation compounds.

For Ru-bip, classical intercalation causes a large distortion of the DNA helix and can lead to base extrusion next to the modification site. However, the local structure of the ruthenated double helix is highly distorted, which is similar to that observed for polycyclic-aromatic-carcinogen- modified DNA adducts. Furthermore, sequence-dependent modification is observed for the Ru-arene complexes and polycyclic-aromatic-carcinogen- modified DNA adducts, but not for platinum complexes with different side-arm intercalators.

The high structural similarity between the dual function Ru-arene lesions and N7-alkylation- intercalation compounds might provide insight into structure-activity relationships for these complexes. These findings help to explain why ruthenium arene complexes have a different mechanism of antitumor activity as compared to cisplatin and are recognized differently by nucleotide repair enzymes.

Conclusion This review has focused on new dual function metal complexes which can interact with DNA by both coordination and intercalation modes of binding. This produces unusual DNA distortions and novel mechanisms of biological activity. Ru-arene complexes with such dual functions e. Ru-bip or Ru-tha are more potent towards cancer cells than their non-intercalating analogs e.

Ru-p-cym or Ru-ben ,36 or less intercalating isomers p-terphenyl arene complexes are more potent than o- or m- terphenyl complexes.

This design concept can be applied to structure-activity relationships for other organometallic anticancer complexes, including cyclopentadienyl complexes Sadler, P. The unusual nature of such DNA distortions affects recognition by DNA binding proteins and repair enzymes and hence the downstream processes related to apoptosis and cancer cell death. His current research focuses on bioinorganic chemistry and biofunctional materials.

His research interests are centered on the chemistry of metals in medicine. Fax: E-mail: liuhongke njnu. E-mail: P. Sadler warwick.