Molecular dynamics simulations of G-DNA and perspectives on the simulation of nucleic acid structures

Šponer, Jiřı́; Cang, Xiaohui; Cheatham, Thomas E.

doi:10.1016/j.ymeth.2012.04.005

Cited by 116 publications

(181 citation statements)

References 205 publications

(228 reference statements)

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“…The first limitation is the time-scale of the simulations. As reviewed elsewhere [49], contemporary simulations are equivalent to hypothetical microsecond-scale single molecule experiments where the molecule initially adopts some starting configuration and subsequently undergoes spontaneous unbiased structural dynamics. In other words, our simulations assess the structural stability of potential G-triplex structures and their lifetimes starting from the folded structure.…”

Section: The Sampling Limitationmentioning

confidence: 99%

“…Any Gquadruplex forming strand can in principle adopt altogether 26 distinct G-quadruplex topologies, differing in strand directionality and type of the loops [22,30]. Although not all of them are energetically feasible, at least five three-quartet (and in addition one two-quartet) topologies have already been observed for the human telomeric quadruplex (see above) as dominant equilibrium structures in various atomistic experiments [12e16, 27,29,35,36,49,63]. Further, the G-rich sequence can potentially form quadruplexes with incomplete number of tetrads, including structures with a slipped strand (actually, the two-quartet quadruplex PDB: 2KF8 [12] falls into this category).…”

Section: Introductionmentioning

confidence: 99%

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Triplex intermediates in folding of human telomeric quadruplexes probed by microsecond-scale molecular dynamics simulations

et al. 2014

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We have carried out extended set of μs-scale explicit solvent MD simulations of all possible G-triplexes which can participate in folding pathways of the human telomeric quadruplex. Our study accumulates almost 60 μs of simulation data, which is by about three orders of magnitude larger sampling compared to the earlier simulations of human telomeric G-DNA triplexes. Starting structures were obtained from experimental quadruplex structures by deleting either the first or the last strand. The life-times of antiparallel triplexes with lateral and diagonal loops are at least on μs-scale, which should be sufficient to contribute to the folding pathways. However, the triplex states may involve structures with various local deviations from the ideal triplexes, such as strand tilting and various alternative and incomplete triads. The simulations reveal easy rearrangements between lateral and diagonal loop triplex topologies. Propeller loops of antiparallel triplexes may to certain extent interfere with the G-triplexes but these structures are still viable candidates to participate in the folding. In contrast, all-parallel all-anti triplexes are very unstable and are unlikely to contribute to the folding. Although our simulations demonstrate that antiparallel G-triplexes, if folded, would have life-times sufficient to participate in the quadruplex folding, the results do not rule out the possibility that the G-triplexes are out-competed by other structures not included in our study. Among them, numerous possible misfolded structures containing guanine quartets can act as off-path intermediates with longer life-times than the triplexes. Besides analyzing the structural dynamics of a diverse set of G-DNA triplexes, we also provide a brief discussion of the limitations of the simulation methodology, which is necessary for proper understanding of the simulation data.

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Section: The Sampling Limitationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Triplex intermediates in folding of human telomeric quadruplexes probed by microsecond-scale molecular dynamics simulations

et al. 2014

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“…In recent years, there has been a growing interest in targeting the DNA G-quadruplex secondary structure formed in the guanine-rich regions in human telomeres and gene promoters for developing novel anti-cancer therapy 1–5 . A G-quadruplex is composed of stacked planar structures (G-tetrads) formed by four hydrogen bonded guanines, with additional stabilizing forces from K + or Na + ions located in the central ion channel of the G-tetrad planes 1 .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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We report the absolute binding free energy calculation and surface plasmon resonance (SPR) experiment for ligand binding with the cMYC G-quadruplex DNA. The unimolecular parallel DNA G-quadruplex formed in the nuclease hypersensitivity element III1 of the c-MYC gene promoter regulates the c-MYC transcription and is recognized as an emerging drug target for cancer therapy. Quindoline derivatives have been shown to stabilize the G-quadruplex and inhibit the c-MYC expression in cancer cells. NMR revealed two binding sites located at the 5′ and 3′ termini of the G-quadruplex. Questions about which site is more favored and the basis for the ligand-induced binding site formation remain unresolved. Here, we employ two absolute binding free energy methods, the double decoupling and the potential of mean force methods, to dissect the ligand binding specificity in the c-MYC G-quadruplex. The calculated absolute binding free energies are in general agreement with the SPR result and suggest that the quindoline has a slight preference for the 5′ site. The flanking residues around the two sites undergo significant reorganization as the ligand unbinds, which provides evidence for ligand-induced binding pocket formation. The results help interpret experimental data and inform rational design of small molecules targeting the c-MYC G-quadruplex.

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“…However, the ligand structures in the two above experiments were really different. Several studies using MM-PBSA method often giving correct trends, however fail to give correct absolute values and often exaggerates the free energy (Šponer, Cang, Cheatham III, 2013). However, in the present study we are able to show the individual energy contributions enabling good understanding in the binding of designed ligands.…”

Section: Free Energy Calculationsmentioning

confidence: 60%

“…There was also issue concerning on biomolecular force field, which did not take into account electronic effect. On the other hand, MM-PBSA method, which is well known in the prediction of binding free energy of ligand-DNA complexes, apply several approximation such as continuum solvent assumption, which neglect atomistic hydration, as well as simplified entropy calculation (Jayaram, Sprous, Young, Beveridge, 1998;Srinivasan, Cheatham III, Cieplak, Kollman, Case, 1998).…”

Section: Resultsmentioning

confidence: 99%

Molecular docking and dynamics simulations on the interaction of cationic porphyrin–anthraquinone hybrids with DNA G-quadruplexes

Arba

Kartasasmita

Tjahjono

2015

Journal of Biomolecular Structure and Dynamics

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A series of cationic porphyrin-anthraquinone hybrids bearing either pyridine, imidazole, or pyrazole rings at the meso-positions have been investigated for their interaction with DNA G-quadruplexes by employing molecular docking and molecular dynamics simulations. Three types of DNA G-quadruplexes were utilized, which comprise parallel, antiparallel, and mixed hybrid topologies. The porphyrin hybrids have a preference to bind with parallel and mixed hybrid structures compared to the antiparallel structure. This preference arises from the end stacking of porphyrin moiety following G-stem and loop binding of anthraquinone tail, which is not found in the antiparallel due to the presence of diagonal and lateral loops that crowd the G-quartet. The binding to the antiparallel, instead, occurred with poorer affinity through both the loop and wide groove. All sites of porphyrin binding were confirmed by 6 ns molecular dynamics simulation, as well as by the negative value of the total binding free energies that were calculated using the MMPBSA method. Free energy analysis shows that the favorable contribution came from the electrostatic term, which supposedly originated from the interaction of either cationic pyridinium, pyrazole, or imidazole groups and the anionic phosphate backbone, and also from the van der Waals energy, which primarily contributed through end stacking interaction.

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Molecular dynamics simulations of G-DNA and perspectives on the simulation of nucleic acid structures

Cited by 116 publications

References 205 publications

Triplex intermediates in folding of human telomeric quadruplexes probed by microsecond-scale molecular dynamics simulations

Triplex intermediates in folding of human telomeric quadruplexes probed by microsecond-scale molecular dynamics simulations

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

Molecular docking and dynamics simulations on the interaction of cationic porphyrin–anthraquinone hybrids with DNA G-quadruplexes

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