Binding modes and pathway of RHPS4 to human telomeric G-quadruplex and duplex DNA probed by all-atom molecular dynamics simulations with explicit solvent

Mulholland, Kelly A.; Siddiquei, Farzana; Wu, Chun

doi:10.1039/c7cp03313c

Cited by 27 publications

(20 citation statements)

References 47 publications

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“… 112 Systematic benchmarking studies up to 1864 crystal complexes have shown that relative MM-GBSA binding energy is a powerful tool to rank ligand binding affinity. 113 − 117 This is also supported by our previous studies, in which the binding energy of between anticancer drug doxorubicin and a B-DNA fragment (d(CGATCG)2), 98 between anticancer drug daunomycin and a TGGGT G-quadruplex DNA, 118 between RHPS4 and human telomeric G-quadruplexes/duplex, 110 between telomestatin and a hybrid telomeric G-quadruplex, 45 and between BRACO19 and a parallel-stranded telomeric G-quadruplex 119 were successfully assessed by this MM-GBSA protocol.…”

Section: Methodssupporting

confidence: 80%

“… 109 Note that the two K + ions inside the G-quadruplex–duplex DNA were kept in MM-GBSA calculations because they were a part of the complex structure. The MM-GBSA binding energy for a system was calculated from three simulations: 110 ligand only, DNA only, and DNA–ligand complex using eq 1 . It has four components in the eq 2 : van der Waals (VDW) interaction energy, hydrophobic interaction energy (SUR), electrostatic interaction (GBELE), and the change of the conformation energy for DNA and ligand.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Methodssupporting

confidence: 80%

Section: Methodsmentioning

confidence: 99%

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

et al. 2018

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“…The highly comparable relative binding energies in both the MM-GBSA and MM-PBSA calculations supports the use of MM-GBSA in ranking the binding poses of BRACO19 in this study. The MM-GBSA binding energy for each system was calculated from three simulations [84]: ligand only, DNA only and DNA-ligand complex using Equation (1). Equation (2) is made up of four components: Van der Waals interaction energy (VDW), hydrophobic interaction energy (SUR), electrostatic interaction (GBELE) and the change of the conformation energy for DNA and ligand.…”

Section: Methodsmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Machireddy

Sullivan

2019

Molecules

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Although BRACO19 is a potent G-quadruplex binder, its potential for clinical usage is hindered by its low selectivity towards DNA G-quadruplex over duplex. High-resolution structures of BRACO19 in complex with neither single-stranded telomeric DNA G-quadruplexes nor B-DNA duplex are available. In this study, the binding pathway of BRACO19 was probed by 27.5 µs molecular dynamics binding simulations with a free ligand (BRACO19) to a DNA duplex and three different topological folds of the human telomeric DNA G-quadruplex (parallel, anti-parallel and hybrid). The most stable binding modes were identified as end stacking and groove binding for the DNA G-quadruplexes and duplex, respectively. Among the three G-quadruplex topologies, the MM-GBSA binding energy analysis suggested that BRACO19′s binding to the parallel scaffold was most energetically favorable. The two lines of conflicting evidence plus our binding energy data suggest conformation-selection mechanism: the relative population shift of three scaffolds upon BRACO19 binding (i.e., an increase of population of parallel scaffold, a decrease of populations of antiparallel and/or hybrid scaffold). This hypothesis appears to be consistent with the fact that BRACO19 was specifically designed based on the structural requirements of the parallel scaffold and has since proven effective against a variety of cancer cell lines as well as toward a number of scaffolds. In addition, this binding mode is only slightly more favorable than BRACO19s binding to the duplex, explaining the low binding selectivity of BRACO19 to G-quadruplexes over duplex DNA. Our detailed analysis suggests that BRACO19′s groove binding mode may not be stable enough to maintain a prolonged binding event and that the groove binding mode may function as an intermediate state preceding a more energetically favorable end stacking pose; base flipping played an important role in enhancing binding interactions, an integral feature of an induced fit binding mechanism.

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“…Spontaneous binding of a ligand to the loops, direct binding to terminal G-quartets and sliding of ligands from the loops along the backbone to the terminal G-quartets has been observed in MD simulations of G4s with other ligands, including telomestatin and BRACO19. [94][95][96][97][98][99][100][101][102] A decisive loop-assisted delivery of RHPS4 to the partially exposed 3quartet of the human telomeric hybrid-1 type G4 has been reported, in which the propeller loop with bound ligand significantly changed its conformation and brought the ligand closer to the quartet (Cf. Supplementary Movie "Hybrid_G4_2HY9_02" in ref.…”

Section: Discussionmentioning

confidence: 99%

Insights into G-Quadruplex–Hemin Dynamics Using Atomistic Simulations: Implications for Reactivity and Folding

Stadlbauer

Islam

Otyepka

et al. 2020

Preprint

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Guanine quadruplex nucleic acids (G4s) are involved in key biological processes such as replication or transcription. Beyond their biological relevance, G4s find applications as biotechnological tools since they readily bind hemin and enhance its peroxidase activity, creating a G4-DNAzyme. The biocatalytic properties of G4-DNAzymes have been thoroughly studied and used for biosensing purposes. Despite hundreds of applications and massive experimental efforts, the atomistic details of the reaction mechanism remain unclear. To help select between the different hypotheses currently under investigation, we use extended explicit-solvent molecular dynamics simulations to scrutinize the G4/hemin interaction. We found that besides the dominant conformation in which hemin is stacked atop the external G-quartets, hemin can also transiently bind to the loops and be brought to the external G-quartets through diverse delivery mechanisms. Importantly, the simulations do not support several mechanistic possibilities (i.e., the wobbling guanine and the iron-bound water molecule) but rather suggest tentative mechanisms in which the external G-quartet itself is responsible for the unique H2O2-promoted biocatalytic properties of the G4/hemin complexes. Our simulations show that once stacked atop a terminal G-quartet, hemin rotates about its vertical axis while readily sampling shifted geometries where the iron transiently contacts oxygen atoms of the adjacent G-quartet. This dynamics is not apparent from the ensemble-averaged structure. We also visualize transient interactions between the stacked hemin and the G4 loops. Finally, we investigated interactions between hemin and on-pathway folding intermediates of the parallel-stranded G4 fold. The simulations suggest that hemin drives the folding of parallel-stranded G4s from slip-stranded intermediates, acting as a G4 chaperone. Limitations of the MD simulation technique are also briefly discussed.Graphical AbstractHemin can bind to G-quadruplex via loop-assisted delivery. The catalytically active structure does not seem to contain an iron-bound water molecule sandwiched in between hemin and G-quadruplex or wobbling guanine.

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Binding modes and pathway of RHPS4 to human telomeric G-quadruplex and duplex DNA probed by all-atom molecular dynamics simulations with explicit solvent

Cited by 27 publications

References 47 publications

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

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

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

Insights into G-Quadruplex–Hemin Dynamics Using Atomistic Simulations: Implications for Reactivity and Folding

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