Structural limitations on the bifunctional intercalation of diacridines into DNA

Wakelin, Laurence P. G.; Romanos, Michael A.; Chen, T. K.; Glaubiger, Daniel; Canellakis, E.S.; Waring, Michael J.

doi:10.1021/bi00616a031

Cited by 113 publications

(110 citation statements)

References 15 publications

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“…The first evidence suggesting violation of the neighborexclusion model was obtained from viscometric studies (12)(13)(14) on interactions between bi-and triderivatives of acridine and DNA, where it was suggested that a single base pair was sandwiched between two acridines. 1H NMR studies on the binding of a series of bis(acridine) compounds to d(AT)5d(AT)5, in which the two acridine rings were linked through linker chains of various lengths, found no evidence of violation of the neighbor-exclusion principle (15,16).…”

mentioning

confidence: 99%

Molecular mechanical simulations on double intercalation of 9-amino acridine into d(CGCGCGC) X d(GCGCGCG): analysis of the physical basis for the neighbor-exclusion principle.

Rao¹,

Kollman²

1987

Proc. Natl. Acad. Sci. U.S.A.

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The neighbor-exclusion principle is one of the most general and interesting rules describing intercalative DNA binding by small molecules. It suggests that such binding can only occur at every other base-pair site, reflecting a very large negative cooperativity in the binding process. We have carried out molecular mechanics and molecular dynamics simulations to study intercalation complexes between 9-amino acridine and the base-paired heptanucleotide d(CGCGCGC) d(GCGCGCG), in which the neighbor-exclusion principle was both obeyed and violated. Our studies find no stereochemical preference that favors the neighbor-exclusion-obeying structures over the neighbor-exclusion-violating structures. Alternative explanations for the existence of the neighbor-exclusion principle are vibrational entropy effects that we calculate to favor the more flexible neighbor-exclusion models over the more rigid neighbor-exclusion-violating models and polyelectrolyte (counterion release) effects.The neighbor-exclusion principle proposed by Crothers (1) is one of the most general rules for intercalative binding of planar drugs to DNA. According to this principle, every second (next-neighbor) intercalation site along the length of the DNA double helix remains unoccupied. Experimental evidence for this principle has been found in fiber diffraction studies on nucleic acid fibers bound to metallointercalative agents (2, 3), in single-crystal studies (4-8) on complexes between dinucleoside monophosphates complexed with intercalating drugs, and solution studies on binding of ethidium ion to oligonucleotides of ribose and deoxyribose sugars (9). Based on earlier crystallographic studies (4-6) that suggested mixed sugar puckering at the intercalation site, a stereochemical basis for the neighbor-exclusion principle was proposed. However, this mixed sugar puckering scheme has not been shown to be essential for creating intercalating sites in double-helical DNA through several crystal structure and model building studies (7-11).The first evidence suggesting violation of the neighborexclusion model was obtained from viscometric studies (12-14) on interactions between bi-and triderivatives of acridine and DNA, where it was suggested that a single base pair was sandwiched between two acridines. 1H NMR studies on the binding of a series of bis(acridine) compounds to d(AT)5d(AT)5, in which the two acridine rings were linked through linker chains of various lengths, found no evidence of violation of the neighbor-exclusion principle (15,16).However, it was also noted that these studies have not ruled out violation of the neighbor-exclusion principle under different salt conditions and temperatures or a different nucleotide sequence (15). It has been postulated (17) that the anticooperativity of ethidium binding to DNA could be explained without reference to the neighbor-exclusion rule and is solely due to polyelectrolyte effects.Why do some simple monofunctional intercalators such as 9-amino acridine not intercalate at neighboring sites and viol...

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mentioning

confidence: 99%

Molecular mechanical simulations on double intercalation of 9-amino acridine into d(CGCGCGC) X d(GCGCGCG): analysis of the physical basis for the neighbor-exclusion principle.

Rao¹,

Kollman²

1987

Proc. Natl. Acad. Sci. U.S.A.

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“…This is in stark contrast to the analogous diacridine series in which bisintercalation is found for the C6 and higher homologues [19]. Indeed, the actual values of the unwinding and extension parameters suggest that the C2 and C7 diquinolines intercalate monofunctionally, whereas the other derivatives are poor intercalators and interact with a fair proportion bound wholly externally.…”

Section: Discussionmentioning

confidence: 67%

Alkyl‐linked diquinolines are monofunctional AT‐selective DNA‐intercalating agents

McFadyen¹,

Denny²,

Wakelin³

1988

FEBS Letters

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The binding of a homologous series of alkyl-linked 4-aminodiquinolines to circular and linear DNAs was studied using viscometric titrations and equilibrium dialysis. The compounds are monofunctional intercalators with the capacity for intercalative binding reaching a peak for the heptane homologue. They show marked AT-base pair selectivity, which suggests that the non-intercalated quinoline ring may lie in the DNA minor groove. Affinities for calf thymus DNA increase as the alkyl chain is lengthened, falling in the range 6 to >250 x l(P M-r in a buffer of Z 0.01. The association constant of the heptane diquinoline decreases with increasing ionic strength, 2.1 cations being released per bound dipositive ligand molecule. All the agents are growth inhibitory towards mouse leukemia cells in culture with IC,, values in the range 0.0618 ,uM.

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“…The viscometric technique is well established as a method for investigating the extension of the DNA helix associated with intercalation [15][16][17][18]. Under conditions where the DNA molecules behave as stiff rods:…”

Section: Methodsmentioning

confidence: 99%

“…This gives the helix extension ratio L/L o = 1 + 2r for monofunctional intercalation and L/L o = 1 + 4r for bifunctional intercalation [ 18], where r represents the binding ratio Effect of eehinomycin on the relative contour length of (a) poly(dA-dT) and (b) poly(dG-dC). The ordinate represents the fractional increase in helix length; the abscissa shows the binding ratio (r), drug molecules bound/nucleotide, calculated from the input ratio (DIP) using the binding parameters in [4].…”

Section: Methodsmentioning

confidence: 99%

“…Mixtures having lower r were generated from these by diluting with DNA in the viscometer. Complexes of ethidium and actinomycin D with the polynucleotides were prepared by direct addition of small amounts of a concentrated drug solution to the DNA in the viscometer as in [18]. Estimates of the binding.ratio, r, were based on published values of association constants and site-sizes in buffer of 10 mM ionic strength [7,12,19].…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Changes in contour length of polydeoxynucleotide fragments

Fox¹,

Harrison²,

Waring³

1981

FEBS Letters

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Structural limitations on the bifunctional intercalation of diacridines into DNA

Cited by 113 publications

References 15 publications

Molecular mechanical simulations on double intercalation of 9-amino acridine into d(CGCGCGC) X d(GCGCGCG): analysis of the physical basis for the neighbor-exclusion principle.

Molecular mechanical simulations on double intercalation of 9-amino acridine into d(CGCGCGC) X d(GCGCGCG): analysis of the physical basis for the neighbor-exclusion principle.

Alkyl‐linked diquinolines are monofunctional AT‐selective DNA‐intercalating agents

Changes in contour length of polydeoxynucleotide fragments

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