Nucleic acids that contain multiple sequential guanines assemble into guanine quadruplexes (G-quadruplexes). Drugs that induce or stabilize G-quadruplexes are of interest because of their potential use as therapeutics. Previously, we reported on the interaction of the Cu(2+) derivative of 5,10,15,20-tetrakis(1-methyl-4-pyridyl)-21H,23H-porphine (CuTMpyP4), with the parallel-stranded G-quadruplexes formed by d(T(4)G( n )T(4)) (n = 4 or 8) (Keating and Szalai in Biochemistry 43:15891-15900, 2004). Here we present further characterization of this system using a series of guanine-rich oligonucleotides: d(T(4)G( n )T(4)) (n = 5-10). Absorption titrations of CuTMpyP4 with all d(T(4)G( n )G(4)) quadruplexes produce approximately the same bathochromicity (8.3 +/- 2 nm) and hypochromicity (46.2-48.6%) of the porphyrin Soret band. Induced emission spectra of CuTMpyP4 with d(T(4)G( n )T(4))(4) quadruplexes indicate that the porphyrin is protected from solvent. Electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry revealed a maximum porphyrin to quadruplex stoichiometry of 2:1 for the shortest (n = 4) and longest (n = 10) quadruplexes. Electron paramagnetic resonance spectroscopy shows that bound CuTMpyP4 occupies magnetically noninteracting sites on the quadruplexes. Consistent with our previous model for d(T(4)G(4)T(4)), we propose that two CuTMpyP4 molecules are externally stacked at each end of the run of guanines in all d(T(4)G( n )T(4)) (n = 4-10) quadruplexes.
G-quadruplexes are formed by association of DNA strands containing multiple contiguous guanines. The capability of drugs to induce formation of or stabilize G-quadruplexes is an active area of investigation. We report the interactions of CuTMpyP4, the Cu(2+) derivative of 5,10,15,20-tetrakis(1-methyl-4-pyridyl)-21H,23H-porphine, with the parallel-stranded G-quadruplexes formed by d(T(4)G(4)T(4)) (1) and d(T(4)G(8)T(4)) (3). Absorption titrations of CuTMpyP4 with (1)(4) or (3)(4) cause both bathochromicity and hypochromicity of the porphyrin Soret band, with larger changes observed for the longer oligonucleotide. An approximate binding constant for (1)(4) and CuTMpyP4 according to the Scatchard model is 5.6 x 10(6) M(-)(1) in terms of quadruplexes and according to the McGhee-von Hippel model is 1.3 x 10(6) M(-)(1) in terms of potential binding sites. An approximate binding constant for (3)(4) and CuTMpyP4 according to the Scatchard model is 5.2 x 10(7) M(-)(1) in terms of quadruplexes and in terms of the McGhee-von Hippel model is 2.4 x 10(6) M(-)(1) in terms of potential binding sites. The site size for CuTMpyP4 and (1)(4) is four using the McGhee-von Hippel model. We find a 2:1 binding stoichiometry for CuTMpyP4 and (1)(4) and a 3:1 binding stoichiometry for CuTMpyP4 and (3)(4) using the method of continuous variation analysis. Induced emission spectra of CuTMpyP4 with (1)(4) or (3)(4) indicate a mode of binding in which the ligand is protected from the solvent. Electron paramagnetic resonance spectra of CuTMpyP4 with added oligonucleotide show an increase in the Cu-N superhyperfine coupling constant as the length of the oligonucleotide increases. On the basis of these data, we propose that for both (1)(4) and (3)(4), CuTMpyP4 molecules externally stack at each end of the run of guanines, similar to other planar G-quadruplex ligands. For (3)(4), our data are consistent with intercalation of a CuTMpyP4 molecule into the G-quadruplex.
In the current review paper the content of the journal Structural Chemistry for the calendar year 2008 is related to thermochemistry. Papers are summarized and a thermochemical slant added. Often questions are asked and research topics suggested.
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