All-atomic simulations on human telomeric G-quadruplex DNA binding with thioflavin T

J Phys Chem B. 2015 Apr 16;119(15):4955-67. doi: 10.1021/acs.jpcb.5b01107. Epub 2015 Apr 6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzothiazoles
  • Computer Simulation
  • DNA / chemistry*
  • G-Quadruplexes*
  • Humans
  • Hydrogen Bonding
  • Models, Genetic
  • Molecular Dynamics Simulation
  • Potassium / chemistry
  • Sodium / chemistry
  • Telomere / chemistry*
  • Thiazoles / chemistry*


  • Benzothiazoles
  • Thiazoles
  • thioflavin T
  • DNA
  • Sodium
  • Potassium