Title

Induction Of G-Quadruplex DNA Structure By Zn(II) 5,10,15,20-Tetrakis (N-Methyl-4-Pyridyl)Porphyrin

Document Type

Article

Publication Date

8-1-2011

Published In

Biochimie

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 mu M oligonucleotide and 100 mM KCl are Delta H = -35 +/- 2 kcal mol(-1) and Delta G(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 similar to 10(6) M(-1) binding constant, determined through UV-vis and ITC titrations. This process is entropically driven and has Delta G(298) of -8.0 kcal mol(-1). TMPyP4 binds with 3:1 stoichiometry and K(a) of similar to 10(6) M(-1). ZnTMPyP4 and TMPyP4 are efficient stabilizers of [d(TAGGG)(2)](2) displaying Delta T(1/2) of 13.5 and 13.8 degrees C, respectively, at 1:2 GQ to porphyrin ratio; CuTMPyP4 shows a much weaker effect (Delta T(1/2) = 4.7 degrees C) and PtTMPyP4 is weakly destabilizing (Delta T(1/2) = -2.9 degrees 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. (C) 2011 Elsevier Masson SAS. All rights reserved.

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