Interaction between G-Quadruplex and Zinc Cationic Porphyrin: The Role of the Axial Water

Abstract

The interaction of ligands with G-quadruplexes has attracted considerable attention due to its importance in molecular recognition and anticancer drugs design. Here, we utilize triplet excited state as a sensitive reporter to study the binding interaction of zinc cationic porphyrin (ZnTMPyP4) with three G-quadruplexes, AG3(T2AG3)3, (G4T4G4)2, and (TG4T)4. By monitoring the triplet decay dynamics of ZnTMPyP4 with transient absorption spectroscopy, the coexisted binding modes via π-π stacking of porphyrin macrocycle and the G-quartets are allowed to be identified quantitatively, which involve intercalation (25% and 36%) versus end-stacking (75% and 64%) for AG3(T2AG3)3 and (G4T4G4)2, and end-stacking (23%) versus partial intercalation (77%) for (TG4T)4. It is shown that the steric hindrance of the axial water decreases greatly the percentage of intercalation. Further, a rapid assessment of binding stoichiometry is fulfilled by measuring the triplet decay dynamics under various [G-quadruplex]/[ZnTMPyP4] ratios. The binding stoichiometric ratios of G-quadruplex/ZnTMPyP4 are 1:2 for AG3(T2AG3)3, 1:1 for (G4T4G4)2, and 1:2 for (TG4T)4, which agree well with results obtained by the conventional method of continuous variation analysis. These results reveal a clear scenario of G-quadruplex/ZnTMPyP4 interaction and provide mechanistic insights for the application of anticancer drug designs using G-quadruplex as target.