Small molecule regulated dynamic structural changes of human G-quadruplexes

Debnath, Manish; Ghosh, Shirsendu; Panda, Deepanjan; Bessi, Irene; Schwalbe, Harald; Bhattacharyya, Kankan

doi:10.1039/c6sc00057f

Cited by 44 publications

(50 citation statements)

References 45 publications

(35 reference statements)

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“…Although the majority of observed folded states are only marginally stable in current conditions, we expect that they can be individually recognized and trapped through selective structure-specific interactions with different ligands (62) and proteins (63). The structural knowledge available through our experiments can potentially be used to control the folding pathway of G4 structures, i.e.…”

Section: Discussionmentioning

confidence: 97%

A direct view of the complex multi-pathway folding of telomeric G-quadruplexes

et al. 2016

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G-quadruplexes (G4s) are DNA secondary structures that are capable of forming and function in vivo. The propensity of G4s to exhibit extreme polymorphism and complex dynamics is likely to influence their cellular function, yet a clear microscopic picture of their folding process is lacking. Here we employed single-molecule FRET microscopy to obtain a direct view of the folding and underlying conformational dynamics of G4s formed by the human telomeric sequence in potassium containing solutions. Our experiments allowed detecting several folded states that are populated in the course of G4 folding and determining their folding energetics and timescales. Combining the single-molecule data with molecular dynamics simulations enabled obtaining a structural description of the experimentally observed folded states. Our work thus provides a comprehensive thermodynamic and kinetic description of the folding of G4s that proceeds through a complex multi-route pathway, involving several marginally stable conformational states.

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Section: Discussionmentioning

confidence: 97%

A direct view of the complex multi-pathway folding of telomeric G-quadruplexes

et al. 2016

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“…The single molecule Förster resonance energy transfer (smFRET) technique provides key information about the structure, relative population distribution of folded or unfolded species, and the end-to-end distance of biomolecules. 23 – 34 The smFRET technique has been used to elucidate the conformational dynamics of G-quadruplexes in the presence of metal ions (K + /Na + ), 28 protein, 33 and small molecules. 34 The population equilibrium of C-rich ILPR and BCL-2 promoter sequences has been studied using laser tweezer experiments.…”

Section: Introductionmentioning

confidence: 99%

“… 23 – 34 The smFRET technique has been used to elucidate the conformational dynamics of G-quadruplexes in the presence of metal ions (K + /Na + ), 28 protein, 33 and small molecules. 34 The population equilibrium of C-rich ILPR and BCL-2 promoter sequences has been studied using laser tweezer experiments. 35 , 36 Majima and co-workers have used smFRET to quantitatively analyse the pH-induced intra-molecular folding dynamics of i-motif DNA.…”

Section: Introductionmentioning

confidence: 99%

Preferential targeting of i-motifs and G-quadruplexes by small molecules

et al. 2017

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“…Because of their promising role as anti-cancer drug targets and sensors, tremendous attention has been paid of late to the synthesis and development of small molecules (ligands) that can specifically target GqDNA structures. Furthermore, several quadruplex-specific ligands have been developed which have been used to detect the structural change and reactivity of quadruplex DNA [30,31], as well as monitor their role in various label-free assays for screening helicase activity [32], protein tyrosine kinase [33], exonuclease activity [34], etc.…”

Section: Introductionmentioning

confidence: 99%

Dispersed dynamics of solvation in G-quadruplex DNA: comparison of dynamic Stokes shifts of probes in parallel and antiparallel quadruplex structures

Singh

Shweta

Sen

2016

Methods Appl. Fluoresc.

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G-quadruplex DNA (GqDNA) structures play an important role in many specific cellular functions and are promising anti-tumor targets for small molecules (ligands). Here, we measured the dynamic Stokes shift of a ligand (Hoechst) bound to parallel c-Myc (mPu22) GqDNA over five decades of time from 100 fs to 10 ns, and compared it with the previously reported dynamics of DAPI bound to antiparallel human telomeric (hTelo22) GqDNA (Pal et al 2015 J. Phys. Chem. Lett. 6 1754). Stokes shift data from fluorescence up-conversion and time-correlated single photon counting experiments was combined to cover the broad dynamic range. The results show that the solvation dynamics of Hoechst in parallel mPu22 GqDNA follow a power law relaxation, added to fast 2 ps exponential relaxation, from 100 fs to 10 ns, with only a subtle difference of power law exponents in the two ligand-GqDNA systems (0.06 in Hoechst-mPu22 compared to 0.16 in DAPI-hTelo22). We measured steady-state fluorescence spectra and time-resolved anisotropy decays which confirm the tight binding of Hoechst to parallel mPu22 with a binding constant of ~1 × 10 M. The molecular docking of Hoechst in parallel GqDNA followed by a 50 ns molecular dynamics (MD) simulation on a Hoechst-GqDNA complex reveals that Hoechst binds to one of the outer G-tetrads by end-stacking near G13 and G4, which is different from the binding site of DAPI inside a groove of antiparallel hTelo22 GqDNA. Reconciling previous experimental and simulation results, we assign the 2 ps component to the hydration dynamics of only weakly perturbed water near mPu22 and the power law relaxation to the coupled motion of water and DNA (i.e. DNA backbone, unpaired bases and loops connecting G-tetrads) which come near the Hoechst inside parallel GqDNA.

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Small molecule regulated dynamic structural changes of human G-quadruplexes

Abstract: A carbazole derivative (BTC) regulates the dynamics of unstructured human c-MYC and h-TELO sequences by folding them into compact quadruplex structures.

Cited by 44 publications

References 45 publications

A direct view of the complex multi-pathway folding of telomeric G-quadruplexes

A direct view of the complex multi-pathway folding of telomeric G-quadruplexes

Preferential targeting of i-motifs and G-quadruplexes by small molecules

Dispersed dynamics of solvation in G-quadruplex DNA: comparison of dynamic Stokes shifts of probes in parallel and antiparallel quadruplex structures

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