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

Abstract

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.

Resolving the Ligand-Binding Specificity in c-MYC G-Quadruplex DNA: Absolute Binding Free Energy Calculations and SPR Experiment

“…Most of the previous computational studies of small molecule binding with nucleic acids have used the end-point method MM-PB(GB)/SA (molecular mechanics-Poisson-Boltzmann/generalized Born/surface area) 31,76–78 . While these studies have provided insights into the energetics of ligand-DNA binding, the MM-PB(GB)/SA method has limited accuracy due to its intrinsic approximation of energy contributions from receptor conformational change and solvent effect 79,80 .…”

Binding of BRACO19 to a Telomeric G-Quadruplex DNA Probed by All-Atom Molecular Dynamics Simulations with Explicit Solvent

“…The nucleic acid simulations have been widely practiced in AMBER DNA force fields [81,98,99,100,101]. In our previous studies, the binding pathway of doxorubicin [101] and Telomestatin [83], anti-cancer drugs to the B-DNA fragment [102] and to the human telomeric hybrid G-quadruplex [83], respectively have been simulated.…”

“…The use of µs-scale simulations with the latest AMBER force fields have shown to provide a good evaluation of the loop conformation of the G-quadruplexes [58]. Using µs-scale simulations with the latest AMBER force fields in our previous work produced detailed and experimentally verified predictions [82,83,84,85,86]. In this work, by using free ligand MD binding simulations with AMBER OL15 DNA and GAFF2 ligand force fields [84] (Table 1), we were able to predict a binding mode of BRACO19 to the double stranded parallel telomeric G-quadruplex that is consistent with the crystal complex structure (PDB ID: 3CE5).…”

TERT—Regulation and Roles in Cancer Formation

“…Telomestatin, BRACO-19, RHPS4, TMPyP4 are some of the most commonly studied G-quadruplex binding proteins ( 191 , 196 , 197 ). Telomestatin (OBP-301) is a natural product isolated from Streptomyces anulatus ( 198 ). The primary mechanism of telomestatin action involves a highly specific interaction with the G-quadruplex to stabilize its structure ( 199 ).…”