Induction of G-quadruplex DNA structure by Zn(II) 5,10,15,20-tetrakis(N- methyl-4-pyridyl)porphyrin

Amlan J. Bhattacharjee, Karan Ahluwalia, Scott Taylor, Ou Jin, John M. Nicoludis, Robert Buscaglia, J. Brad Chaires, David J.P. Kornfilt, David G.S. Marquardt, Liliya A. Yatsunyk

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

G-quadruplexes (GQ) are formed by the association of guanine-rich stretches of DNA. Certain small molecules can influence kinetics and thermodynamics of this association. Understanding the mechanism of ligand-assisted GQ folding is necessary for the design of more efficient cancer therapeutics. The oligonucleotide d(TAGGG) 2 forms parallel bimolecular GQ in the presence of ≥66 mM K +; GQs are not formed under Na +, Li + or low K + conditions. The thermodynamic parameters for GQ folding at 60 μM oligonucleotide and 100 mM KCl are ΔH = -35 ± 2 kcal mol -1 and ΔG 310 = -1.4 kcal mol -1. Quadruplex [d(TAGGG) 2] 2 binds 2-3 K + ions with K d of 0.5 ± 0.2 mM. Our work addresses the question of whether metal free 5,10,15,20-tetrakis(N-methyl-4-pyridyl) porphyrin (TMPyP4) and its Zn(II), Cu(II), and Pt(II) derivatives are capable of facilitating GQ folding of d(TAGGG) 2 from single stranded, or binding to preformed GQ, using UV-vis and circular dichroism (CD) spectroscopies. ZnTMPyP4 is unique among other porphyrins in its ability to induce GQ structure of d(TAGGG) 2, which also requires at least a low amount of potassium. ZnTMPyP4 binds with 2:1 stoichiometry possibly in an end-stacking mode with a ∼10 6 M -1 binding constant, determined through UV-vis and ITC titrations. This process is entropically driven and has ΔG 298 of -8.0 kcal mol -1. TMPyP4 binds with 3:1 stoichiometry and K a of ∼10 6 M -1. ZnTMPyP4 and TMPyP4 are efficient stabilizers of [d(TAGGG) 2] 2 displaying ΔT 1/2 of 13.5 and 13.8 °C, respectively, at 1:2 GQ to porphyrin ratio; CuTMPyP4 shows a much weaker effect (ΔT 1/2 = 4.7 °C) and PtTMPyP4 is weakly destabilizing (ΔT 1/2 = -2.9 °C). The selectivity of ZnTMPyP4 for GQ versus dsDNA is comparable to that of TMPyP4. The ability of ZnTMPyP4 to bind and stabilize GQ, to induce GQ formation, and speed up its folding may suggest an important biological activity for this molecule.

Original languageEnglish (US)
Pages (from-to)1297-1309
Number of pages13
JournalBiochimie
Volume93
Issue number8
DOIs
StatePublished - Aug 2011
Externally publishedYes

Keywords

  • CD
  • G-quadruplex
  • Metalloporphyrin
  • Quadruplex folding
  • Zn(II)

ASJC Scopus subject areas

  • Biochemistry

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