Probing the Binding Pathway of BRACO19 to a Parallel-Stranded Human Telomeric G-Quadruplex Using Molecular Dynamics Binding Simulation with AMBER DNA OL15 and Ligand GAFF2 Force Fields

• DOI: 10.1021/acs.jcim.7b00287
• Publication Date: 2017-10-13T19:38:01Z
• Authors: Babitha Machireddy; Gurmannat Kalra; Subash Jonnalagadda; Kandalam Ramanuja...; Chun Wu
• Keywords: G-quadruplex

Human telomeric DNA G-quadruplex has been identified as a good therapeutic target in cancer treatment. G-quadruplex-specific ligands that stabilize the have great potential to be developed anticancer agents. Two crystal structures (an apo form of parallel stranded human and its holo complex with BRACO19, potent ligand) solved, yet binding mechanism pathway remain elusive. In this study, we simulated free BRACO19 molecule using latest AMBER (OL15) ligand (GAFF2) force fields. Three modes identified: top stacking, bottom intercalation, groove binding. Bottom intercalation (51% population) resembles pose structure very well. The mode is less stable than likely an intermediate state leading mode. A flip–insertion was observed mode, during which flipping bases outward makes space for insertion, after flip back increase stability complex. addition reproducing base-flipping behavior some loop residues upon binding, direct alignment type ATAT-tetrad our simulations first time. These successes provide initial support combination OL15 GAFF2 fields study quadruplex–ligand interactions.