Binding of Telomestatin, TMPyP4, BSU6037, and BRACO19 to a Telomeric G-Quadruplex–Duplex Hybrid Probed by All-Atom Molecular Dynamics Simulations with Explicit Solvent

Abstract

A promising anticancer therapeutic strategy is the stabilization of telomeric G-quadruplexes using G-quadruplex-binding small molecules. Although many G-quadruplex-specific ligands have been developed, their low potency and selectivity to G-quadruplexes over duplex remains unsolved. Recently, a crystal structure of a telomeric 3′ quadruplex–duplex hybrid was reported and the quadruplex–duplex interface was suggested to a good target to address the issues. However, there are no high-resolution complex structures reported for G-quadruplex ligands except for a docked BSU6037. In this study, molecular dynamic (MD) binding simulations with a free ligand were used to study binding poses and dynamics of four representative ligands: telomestatin, TMPyP4, BSU6037, and BRACO19. The MD data showed that BSU6037 was able to fully intercalate into the interface whereas TMPyP4 and BRACO19 could only maintain partial intercalation into the interface and telomestatin only binds at the quadruplex and duplex ends. Both linear ligands, BSU6037 and BRACO19, were able to interact with the interface, yet they were not selective over duplex DNA. The DNA geometry, binding modes, and binding pathways were systematically characterized, and the binding energy was calculated and compared for each system. The interaction of the ligands to the interface was by the means of an induced-fit binding mechanism rather than a lock–key mechanism, consisting of the DNA unfolding at the interface to allow entrance of the drug and then the refolding and repacking of the DNA and the ligand to further stabilize the G-quadruplex. On the basis of the findings in this study, modifications were suggested to optimize the interface binding for TMPyp4 and telomestatin.

TERRA G-quadruplex RNA interaction with TRF2 GAR domain is required for telomere integrity

“…1 ). NMM is reported to have high selectivity to G4 DNA over other DNA structures and bind selectively to parallel forms of G4 DNA 54 , 57 , 86 . TERRA is reported to form a parallel stranded G4 32 , 87 , and also to have a high affinity for related porphyrins, such as TMPyP4 88 .…”

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

“…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).…”

Spectroscopic and In Silico Studies on the Interaction of Substituted Pyrazolo[1,2-a]benzo[1,2,3,4]tetrazine-3-one Derivatives with c-Myc G4-DNA

“…As illustrated in Figure 10 b, the sliding between the two quartets can be facilitated by interactions with the bases in the loops. Interactions between the loops’ bases and a variety of ligands, such as hemin, pentacyclic acridine compound RHPS4, Telomestatin, porphyrins derivative TMPyP4, benzothiazole-based CX-5461, the tri-substituted acridine BRACO19, Thioflavin T, and other ligands, have already been observed in recent studies by Stadlbauer et al [ 38 ], Mulholland et al [ 39 ], Sullivan et al [ 40 , 41 ], Machireddy et al [ 42 , 43 ], and Luo et al [ 44 ].…”