Understanding binding interactions of cationic porphyrins with B-form DNA

The DNA-binding interactions of 5,10,15,20-tetra(N-methylpyridinium-4-yl)porphyrin, herein denoted H(2)T4, and related cationic porphyrins have long been of interest because of the potential for therapeutic applications and the novel binding interactions observed with DNA. A brief review of available physical studies reveals that the monomeric porphyrin can bind either externally, or by intercalation, depending on the nature of the DNA substrate. Coulombic, interactions, van der Waals' forces, and hydrophobic effects provide for stability of the adduct, while the pyridiniumyl substituents and axial ligands on metalated forms pose important steric constraints. Competitive binding studies involving DNA hairpin substrates reveal that the base composition, not the sequence, dictates the mode of binding. An overarching principle is that relatively rigid stretches,of DNA, i.e., runs containing 50 % or more G&3bond; C base pairs, do not support high-affinity external binding. Instead, H(2)T4 binds by intercalation despite unfavorable steric contacts that arise within the minor groove. The same pattern holds true for Cu(T4) and other metalated forms lacking axial ligands. New results presented include structures of a pair of less bulky, disubstituted porphyrins, H(2)D3n (5,15-di(3-pyridyl)porphyrin). and H(2)D4 (5,15-di(N-methylpyridinium-4-yl)porphyrin), both of which intercalate into.