Effects of Cationic Charge on Three-Dimensional Structures of Intercalative Complexes Structure of a bis-Intercalated DNA Complex Solved by MAD Phasing

Abstract

We characterize intercalative complexes as either "high charge" and "low charge". In low charge complexes, stacking interactions appear to dominate stability and structure. The dominance of stacking is evident in structures of daunomycin, nogalamycin, ethidium, and triostin A/echinomycin. By contrast in a DNA complex with the tetracationic metalloporphyrin CuTMPyP4 [copper (II) meso-tetra(N-methyl-4-pyridyl)porphyrin], electrostatic interactions appear to draw the porphyrin into the duplex interior, extending the DNA along its axis, and unstacking the DNA. Similarly, DNA complexes of tetracationic ditercalinium and tetracationic flexi-di show significant unstacking. Here we report x-ray structures of complexes of the tetracationic bis-intercalator D232 bound to DNA fragments d(CGTACG) and d(BrCGTABrCG). D232 is analogous to ditercalinium but with three methylene groups inserted between the piperidinium groups. The extension of the D232 linker allows it to sandwich four base pairs rather than two. In comparison to CuTMPyP4, flexi-di and ditercalinium, stacking interactions of D232 are significantly improved. We conclude that it is not sufficient to characterize intercalators simply by net charge. One anticipates strong electrostatic forces when cationic charge is focused to a small volume or region near DNA and so must consider the extent to which cationic charge is focused or distributed. In sum, ditercalinium, with a relatively short linker, focuses cationic charge more narrowly than does D232. So even though the net charges are equivalent, electrostatic charges are expected to be of greater structural significance in the ditercalinium complex than in the D232 complex.

Molecular modeling of tricyclic compounds with anilino substituents and their intercalation complexes with DNA sequences

“…Comp ta (8) tb ( important stabilizing factor [25,26]. LUMO and HOMO energy values are related to the substituents present in the anilino ring, as expected, with lower values in those compounds with electronwithdrawing groups.…”

Oligo- and polypeptide conjugates of cationic porphyrins: binding, cellular uptake, and cellular localization

“…It was shown that out of water-soluble tetra-cationic 5,10,15‚20-tetra(N-methylpyridinium-4-yl)porphyrin (TMPyP) naturally drawn to the DNA polyanion, tri-or dicationic derivatives also bind to DNA by intercalation or by external binding (Pasternack et al 1983;Shui et al 2000;Zupan et al 2004;D'Urso et al 2009;Gong et al 2012;Accetta et al 2015).…”

PT-ACRAMTU, A Platinum–Acridine Anticancer Agent, Lengthens and Aggregates, but does not Stiffen or Soften DNA

“…Using laser tweezers, Baumann et al showed reduced stiffness in DNA due to interaction with monovalent and multivalent cations (46). Shiu et al suggest that in high charge intercalators (2+ or higher), the electrostatic interactions play a larger role in complex stability and may cause some unstacking, whereas in low charge intercalators stacking interactions appear to dominate the stability of the intercalator (47). Thus, in conclusion, it appears that each intercalator needs to be analyzed individually in terms of their effect on the DNA structure, stability and DNA persistence length.…”