jp5b01107_si_001.pdf (2.83 MB)
All-Atomic Simulations on Human Telomeric G‑Quadruplex DNA Binding with Thioflavin T
journal contribution
posted on 2015-04-16, 00:00 authored by Di Luo, Yuguang MuLigand-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.