title: All-atomic simulations on human telomeric G-quadruplex DNA binding with thioflavin T.
abstract: Ligand-stabilized human telomeric G-quadruplex DNA is believed to be an anticancer agent, as it can impede the continuous elongation of telomeres by telomerase in cancer cells. In this study, five well-established human telomeric G-quadruplex DNA models were probed on their binding behaviors with thioflavin T (ThT) via both conventional molecular dynamics (MD) and well-tempered metadynamics (WT-MetaD) simulations. Novel dynamics and characteristic binding patterns were disclosed by the MD simulations. It was observed that the K(+) promoted parallel and hybridized human telomeric G-quadruplex conformations pose higher binding affinities to ThT than the Na(+) and K(+) promoted basket conformations. It is the end, sandwich, and base stacking driven by π-π interactions that are identified as the major binding mechanisms. As the most energy favorable binding mode, the sandwich stacking observed in (3 + 1) hybridized form 1 G-quadruplex conformation is triggered by reversible conformational change of the G-quadruplex. To further examine the free energy landscapes, WT-MetaD simulations were utilized on G-quadruplex-ThT systems. It is found that all of the major binding modes predicted by the MD simulations are confirmed by the WT-MetaD simulations. The results in this work not only accord with existing experimental findings, but also reinforce our understanding on the dynamics of G-quadruplexes and aid future drug developments for G-quadruplex stabilization ligands.
authors: School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
authors: Di
authors: D
authors: Luo
authors: School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
authors: Yuguang
authors: Y
authors: Mu
mesh_terms: D052160:Benzothiazoles; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry*; D054856:G-Quadruplexes; D006801:Humans; D006860:Hydrogen Bonding; D008957:Models, Genetic; D056004:Molecular Dynamics Simulation; D011188:Potassium / Q000737:chemistry; D012964:Sodium / Q000737:chemistry; D016615:Telomere / Q000737:chemistry*; D013844:Thiazoles / Q000737:chemistry*
chemical_list: D052160:Benzothiazoles; D013844:Thiazoles; C009462:thioflavin T; D004247:DNA; D012964:Sodium; D011188:Potassium