Resolving the Ligand-Binding Specificity in c-MYC G-Quadruplex DNA: Absolute Binding Free Energy Calculations and SPR Experiment

5 years ago

Resolving the Ligand-Binding Specificity in c-MYC G-Quadruplex DNA: Absolute Binding Free Energy Calculations and SPR Experiment

Clement Lin, Piotr Cieplak, Lauren Wickstrom, Nanjie Deng, Danzhou Yang

We report the absolute binding free energy calculation and surface plasmon resonance (SPR) experiment for ligand binding with the c-MYC G-quadruplex DNA. The unimolecular parallel DNA G-quadruplex formed in nuclease hypersensitivity element III₁ of the c-MYC gene promoter regulates the c-MYC transcription and is recognized as an emerging drug target for cancer therapy. Quindoline derivatives have been shown to stabilize the G-quadruplex and inhibit the c-MYC expression in cancer cells. NMR revealed two binding sites located at the 5′ and 3′ termini of the G-quadruplex. Questions about which site is more favored and the basis for the ligand-induced binding site formation remain unresolved. Here, we employ two absolute binding free energy methods, the double decoupling and the potential of mean force methods, to dissect the ligand-binding specificity in the c-MYC G-quadruplex. The calculated absolute binding free energies are in general agreement with the SPR result and suggest that quindoline has a slight preference for the 5′ site. The flanking residues around the two sites undergo significant reorganization as the ligand unbinds, which provides evidence for ligand-induced binding pocket formation. The results help interpret experimental data and inform rational design of small molecules targeting the c-MYC G-quadruplex.

Publisher URL: http://dx.doi.org/10.1021/acs.jpcb.7b09406

DOI: 10.1021/acs.jpcb.7b09406