Molecular insight into the selective binding between human telomere G-quadruplex and a negatively charged stabilizer

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• Human telomeres feature single-stranded overhangs that form G-quadruplex (G4) structures.
• Stabilizing telomere G4s is a potential anti-cancer strategy by inhibiting telomerase-mediated lengthening.

Purpose of the Study:

• To investigate the atomic-level binding interactions of anionic phthalocyanine 3,4',4'',4'''-tetrasulfonic acid (APC) with human telomere hybrid G4s.
• To evaluate the potential of APC as a selective telomere G4 stabilizer for cancer therapy.

Main Methods:

• Molecular docking simulations
• Molecular dynamics (MD) simulations
• Analysis of non-covalent interactions and binding free energy decomposition

Main Results:

• APC demonstrated preferential end-stacking binding to the hybrid type II (hybrid-II) telomere G4 over groove binding to the hybrid type I (hybrid-I) G4.
• APC binding resulted in significant stabilization of hybrid-II G4 and more favorable binding free energies.
• Van der Waals interactions were identified as the primary force driving APC binding to telomere G4s.

Conclusions:

• APC selectively binds and stabilizes human telomere G4 structures, particularly hybrid-II.
• The findings provide crucial insights for designing novel, selective telomere G4 stabilizers for cancer treatment.