A thymine tetrad in d(TGGGGT) quadruplexes stabilized with Tl+/Na+ ions

Cáceres, Carmen Victoria; Wright, G.; Gouyette, Catherine; Parkinson, Gary N.; Subirana, Juan A.

doi:10.1093/nar/gkh269

Cited by 102 publications

(98 citation statements)

References 31 publications

(39 reference statements)

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“…For the gas-phase MD simulations, the initial structure of G1 was taken from a parallel-stranded crystal structure resolved at 0.95 Å (PDB: 1S45) [39], and the starting structure of G3 was taken from an antiparallel-stranded crystal structure resolved at 1.86 Å (PDB: 1JB7) [40]. For G4 -G7, a parallel-stranded crystal structure resolved at 2.1 Å (PDB 1KFI) [41] and an antiparallel-stranded NMR structure (PDB 143D) [42] were applied as templates to construct the initial structures of both strand orientations for each G-quadruplex.…”

Section: Starting Geometriesmentioning

confidence: 99%

Gas-phase stability of G-quadruplex DNA determined by electrospray ionization tandem mass spectrometry and molecular dynamics simulations

Mazzitelli

Wang²,

Smith

et al. 2007

J. Am. Soc. Mass Spectrom.

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) 4 , were investigated using molecular dynamics simulations and electrospray ionization mass spectrometry (ESI-MS). MD simulations revealed that the G-quadruplexes maintained their structures in the gas phase although the G-quartets were distorted to some degree and ammonium ions, retained by [d(TG 4 T)] 4 and [d(T 2 G 3 T)] 4 , played a key role in stabilizing the tetrad structure. Energyvariable collisional activated dissociation was used to assess the relative stabilities of each quadruplex based on E 1/2 values, and the resulting order of relative stabilities was found to beThe stabilities from the E 1/2 values generally paralleled the RMSD and relative free energies of the quadruplexes based on the MD energy analysis. One exception to the general agreement is [d(G 4 T 4 G 4 )] 2 , which had the lowest E 1/2 value, but was determined to be the most stable quadruplex according to the free-energy analysis and ranked fourth based on the RMSD comparison. This discrepancy is attributed to differences in the fragmentation pathway of the quadruplex. T he basis of many anticancer and antitumor therapies is the interaction between small molecule drugs and nucleic acid structures. While most current DNA-interactive therapies target duplex DNA, G-quadruplex DNA has attracted recent interest as a potential anti-cancer drug target because of its role in telomere maintenance [1][2][3]. Telomeres are the regions of non-coding DNA found on the extremities of chromosomes [4]. In addition to protecting the chromosomes from fusion and degradation, telomeres allow for the complete replication of the chromosomal DNA. With each subsequent cell division process, the length of the telomeres is shortened until a critical length is reached, leading to cell senescence and death [5]. Telomerase is a reverse transcriptase enzyme that is responsible for maintaining the length of telomeric DNA. While this enzyme is inactive in most human somatic cells, high levels of telomerase activity are found in 80% to 90% of human cancer cells [6,7].Telomeric DNA is composed of tandem repeats of G-rich sequences, such as the d(T 2 AG 3 ) n sequence in mammals [8], d(T 2 G 4 ) n in Tetrahymena [9], and d(T 4 G 4 ) n in Oxytricha [10]. These and other G-rich sequences have been shown to form G-quadruplex structures in vitro. G-quadruplex DNA forms via Hoogsteen hydrogen bonding between a planar arrangement of four guanine nucleobases, termed a G-quartet. In the quadruplex structure, the G-quartets stack on top of one another and the overall structure is stabilized by monovalent cations such as Na ϩ , K ϩ , or NH 4 ϩ coordinated in the central cavity of the tetrad [11]. Structural polymorphism resulting from different quadruplex sequences and strand orientations has been demonstrated in vitro [12]. A DNA sequence containing a single G-rich repeat can form a four-stranded parallel G-quadruplex. Strands containing two or more G-rich regions can form G-G hairpins and dimerize in different orientations to form a two-stranded quadruplex, while a sequence w...

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Section: Starting Geometriesmentioning

confidence: 99%

Gas-phase stability of G-quadruplex DNA determined by electrospray ionization tandem mass spectrometry and molecular dynamics simulations

Mazzitelli

Wang²,

Smith

et al. 2007

J. Am. Soc. Mass Spectrom.

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“…[9][10][11] One of the objectives of this project was to investigate if we could expand the structural repertoire of RNA quadruplexes and obtain novel RNA G4 folds by using a "forced-strand approach".…”

Section: Introductionmentioning

confidence: 99%

Orienting Tetramolecular G‐Quadruplex Formation: The Quest for the Elusive RNA Antiparallel Quadruplex

Mendoza

Porrini

Salgado

et al. 2015

Chemistry A European J

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DNA and RNA G-quadruplexes (G4) are unusual nucleic acid structures involved in a number of key biological processes. RNA G-quadruplexes are less studied although recent evidence demonstrates that they are biologically relevant. Compared to DNA quadruplexes, RNA G4 are generally more stable and less polymorphic. Duplexes and quadruplexes may be combined to obtain pure tetrameric species. Here, we investigated whether classical antiparallel duplexes can drive the formation of antiparallel tetramolecular quadruplexes. This concept was first successfully applied to DNA G4. In contrast, RNA G4 were found to be much more unwilling to adopt the forced antiparallel orientation, highlighting that the reason RNA adopts a different structure must not be sought in the loops but in the G-stem structure itself. RNA antiparallel G4 formation is likely to be restricted to a very small set of peculiar sequences, in which other structural features overcome the formidable intrinsic barrier preventing its formation.

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“…We chose the parallel-stranded [dTGGGGT] 4 G-quadruplex DNA structure ( Fig. 1) because (1) starting atomic coordinates of [dTGGGGT] 4 are available from X-ray crystallography, [11][12][13][14] (2) the same molecular assembly was studied by nuclear magnetic resonance (NMR) as well and presents the same G-quadruplex core arrangement, although the thymine placement differs, with evidence for T-T interactions, [15][16][17] and (3) the central guanine-rich core remains very rigid in the gas phase, [18][19][20][21] thanks to the preservation of the G-quartet hydrogen bonds and to the coordination of three 711 ammonium cations in-between the four guanine G-quartets. Only the position of thymines in the gas phase is less certain.…”

Section: Introductionmentioning

confidence: 99%

Linking molecular models with ion mobility experiments. Illustration with a rigid nucleic acid structure

D’Atri¹,

Porrini²,

Rosu³

et al. 2015

J. Mass Spectrom.

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Ion mobility spectrometry experiments allow the mass spectrometrist to determine an ion's rotationally averaged collision cross section Ω EXP . Molecular modelling is used to visualize what ion three-dimensional structure(s) is(are) compatible with the experiment. The collision cross sections of candidate molecular models have to be calculated, and the resulting Ω CALC are compared with the experimental data. Researchers who want to apply this strategy to a new type of molecule face many questions: (1) What experimental error is associated with Ω EXP determination, and how to estimate it (in particular when using a calibration for traveling wave ion guides)? (2) How to generate plausible 3D models in the gas phase? (3) Different collision cross section calculation models exist, which have been developed for other analytes than mine. Which one(s) can I apply to my systems? To apply ion mobility spectrometry to nucleic acid structural characterization, we explored each of these questions using a rigid structure which we know is preserved in the gas phase: the tetramolecular G-quadruplex [dTGGGGT] 4 , and we will present these detailed investigation in this tutorial. Additional supporting information may be found in the online version of this article at the publisher's web site.Keywords: ion mobility spectrometry; collision cross section; structure; nucleic acids; simulations; molecular modeling; gas-phase ion structure IntroductionElectrospray mass spectrometry (ESI-MS) in native conditions can preserve the structures of biomolecules and separate them according to their mass-to-charge ratios. [1,2] Ion mobility spectrometry (IMS) separates ions according to their size-to-charge ratios in the gas-phase. [3][4][5][6] Size is related to the mass (or number of atoms) and to the three-dimensional shape of a molecule. Therefore, by hyphenating IMS to mass spectrometry (IM-MS), one can sort ions according to both mass and shape. The challenge is to decipher structural information from ion mobility experiments. [7][8][9] The physical quantity characterizing the shape is the collision cross section (CCS), [10] which will be introduced in more detail in the Section on Ion mobility and collision cross sections. The present tutorial clarifies how to interpret CCS measurements in terms of three-dimensional structure for ions larger than 100 atoms extracted from the solution by electrospray ionization (ESI). The gold standard is to match CCSs experimentally obtained from IMS with CCSs calculated for modelling three-dimensional structures of the ion of interest. We will discuss the factors that can affect the precision (reproducibility) and accuracy in both the measurements and the calculations. Understanding each of these factors is crucial to interpret quantitative matches confidently and assess the meaningfulness of structural assignments.On the experimental side, we will describe the determination of CCS from traveling wave ion mobility spectrometers and from drift tube ion mobility spectrometers, with example data recorde...

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A thymine tetrad in d(TGGGGT) quadruplexes stabilized with Tl+/Na+ ions

Cited by 102 publications

References 31 publications

Gas-phase stability of G-quadruplex DNA determined by electrospray ionization tandem mass spectrometry and molecular dynamics simulations

Gas-phase stability of G-quadruplex DNA determined by electrospray ionization tandem mass spectrometry and molecular dynamics simulations

Orienting Tetramolecular G‐Quadruplex Formation: The Quest for the Elusive RNA Antiparallel Quadruplex

Linking molecular models with ion mobility experiments. Illustration with a rigid nucleic acid structure

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