Intercalative G-tetraplex stabilization of telomeric DNA by a cationic porphyrin

被引:238
作者
Haq, I
Trent, JO
Chowdhry, BZ
Jenkins, TC
机构
[1] Univ Greenwich, Sch Chem & Life Sci, London SE18 6PF, England
[2] Univ Alabama Birmingham, Dept Med, Div Hematol Oncol, Birmingham, AL 35294 USA
关键词
D O I
10.1021/ja981554t
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
DNA tetraplex ("quadruplex") structures formed from guanine tetrads and significant to the regulation of telomerase activity have recently been shown to be stabilized by interaction with a cationic porphyrin [Anantha, N. V.; Azam, M.; Sheardy, R. D. Biochemistry 1998, 37, 2709-2714. Wheelhouse, R. T.; Sun, D.; Han, Il.; Han, F. X.; Hurley, L. H. J. Am. Chem. Sec. 1998, 120, 3261-3262]. Porphyrin binding to DNA sequences from the Oxytricha and human telomeres and a thrombin-binding aptamer is here examined by isothermal titration calorimetry (ITC) and spectrophotometry under conditions that favor self-assembly to their respective intermolecular or intramolecular tetraplex structures. Analysis of the ITC and optical data reveals (i) saturating porphyrin/tetraplex binding stoichiometries of 1:1, 2:1, and 3:1 for d(G(2)T(2)G(2)TGTG(2)T(2)G(2)), d(AG(3)[T(2)AG(3)](3)), and [d(T(4)G(4))](4), respectively, involving near-equivalent sites, (ii) weak binding of only (0.3-2) x 10(5) M-1 per site, and (iii) no evidence for stepwise complexation in solutions containing K+ ions. This stoichiometry is maintained in Na+ solutions, if the tetraplex is stable, but nondegenerate sites are implicated for the 2:1 and 3:1 complexes where the first porphyrin binds with 20-40-fold greater affinity than any subsequent ligand(s). Importantly, the stoichiometries correspond to the number of intervals between successive G-tetrad planes in each tetraplex. The results indicate binding by threading intercalation at each closely similar GpG site, possibly without Invoking neighbor exclusion for adjacent sites, rather than through either external electrostatic processes or end-pasted stacking modes. This mechanism is supported by dynamic molecular modeling simulations with two DNA tetraplexes which show that stable intercalated complexes can be realized. A plausible model is developed that accounts for the occupation of adjacent sites, where unfavorable interligand contacts are avoided by phased asymmetric positioning of the porphyrin molecules within each G-tetrad intercalation pocket.
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页码:1768 / 1779
页数:12
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