Abstract
Telomere DNA assumes a high-order G-quadruplex (G4) structure, stabilization of which prevents telomere lengthening by telomerase in cancer. Through applying combined molecular simulation methods, an investigation on the selective binding mechanism of anionic phthalocyanine 3,4',4'',4'''-tetrasulfonic acid (APC) and human hybrid (3 + 1) G4s was firstly performed at the atomic level. Compared to the groove binding mode of APC and the hybrid type I (hybrid-I) telomere G4, APC preferred to bind to the hybrid type II (hybrid-II) telomere G4 via end-stacking interactions, which showed much more favorable binding free energies. Analyses of the non-covalent interaction and binding free energy decomposition revealed a decisive role of van der Waals interaction in the binding of APC and telomere hybrid G4s. And the binding of APC and hybrid-II G4 that showed the highest binding affinity adopted the end-stacking binding mode to form the most extensive van der Waals interactions. These findings add new knowledge to the design of selective stabilizers targeting telomere G4 in cancer.