Binding of Telomestatin to a Telomeric G‑Quadruplex DNA Probed by All-Atom Molecular Dynamics Simulations with Explicit Solvent

Telomestatin, a natural
product isolated from Streptomyces
anulatus, stabilizes telomeric DNA G-quadruplexes.
Treatment with this ligand induces apoptosis of various cancer cells
with a relatively low effect on somatic cells because of its high
selectivity toward G-quadruplex over duplex DNA. A high-resolution
structure of a G-quadruplex in complex with telomestatin does not
yet exist because of its low solubility, and the binding nature of
this ligand remains elusive. In this study, we utilized molecular
binding simulations and MMGBSA binding energy analysis to decipher
the nature of the binding of telomestatin to a telomeric G-quadruplex.
We identified three major binding poses: bottom intercalation, top
stacking, and groove binding. The top stacking mode resembles the
pose observed in an NMR complex of the same G-quadruplex with the
telomestatin analogue L2H. The bottom intercalation and groove binding
poses were not observed in the previous studies of L2H. The bottom
intercalation mode exhibited the most favorable binding energy among
the three modes, while also partially intercalating into the telomeric
quadruplex. The dynamic and energetic properties of these three binding
modes are thoroughly examined. “Flip insertion” and
“slide insertion” were observed in the bottom intercalation
mode. Our findings also provide insight into the design of more selective
DNA quadruplex ligands as anticancer agents in the future.