Molecular insights into the selective binding mechanism targeting parallel human telomeric G-quadruplex.

Stabilizing human telomere DNA G-quadruplex (G4) proves a promising anti-cancer strategy. Though plenty of G4 stabilizing molecules have been reported, little is known about their selective binding mechanism among various G4s. Recently, a designed monohydrazone derivative (compound 15) was reported to display specific preference in binding and stabilizing parallel human telomeric G4. To reveal the selective binding mechanism, a comparative theoretical investigation was performed on two monohydrazone derivatives (compounds 1 and 15) and three telomeric G4s showing parallel, hybrid-I, and hybrid-II conformations. Two probable binding modes, i.e. the end-stacking binding and the groove binding, were predicted by molecular dockings for each monohydrazone in its binding with the telomeric G4s. Further long-timescale molecular dynamics simulations reveal the conversion from the groove binding to the end-stacking binding for both compounds, indicating the preference of the end-stacking binding mode. Structural analysis together with binding free energy calculations show that the van der Waals interaction plays a leading role in ranking the binding affinity. By forming extensive van der Waals interactions, the parallel G4-15 binding complex shows the highest binding affinity, and the corresponding compound 15 exhibits the strongest stabilizing effect to the telomeric G4. These findings agree well with the experimental observations. Through characterizing the selective binding between monohydrazones and telomeric G4s at the atomic level, the current study provides support to the design of novel selective stabilizers targeting telomeric G4s.