Evaluation of DNA/Ligand Interactions by Electrospray Ionization Mass Spectrometry

Brodbelt, Jennifer S.

doi:10.1146/annurev.anchem.111808.073627

Cited by 42 publications

(41 citation statements)

References 64 publications

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“…A recent review comprehensively covers the literature on mass spectrometry of G-quadruplex DNA until 2009 [8]. Other recent reviews on the characterisation of DNA-ligand interactions by mass spectrometry include extensive discussion of ligand binding to G-quadruplexes [9,10]. In the present contribution, we decided to explain in detail the mass spectrometry-based methodologies we currently apply routinely for G-quadruplex analysis (with no ligand attached).…”

Section: Introductionmentioning

confidence: 99%

Mass spectrometry and ion mobility spectrometry of G-quadruplexes. A study of solvent effects on dimer formation and structural transitions in the telomeric DNA sequence d(TAGGGTTAGGGT)

Ferreira

Marchand

Gabelica

2012

Methods

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We survey here state of the art mass spectrometry methodologies for investigating G-quadruplexes, and will illustrate them with a new study on a simple model system: the dimeric G-quadruplex of the 12-mer telomeric DNA sequence d(TAGGGTTAGGGT), which can adopt either a parallel or an antiparallel structure. We will discuss the solution conditions compatible with electrospray ionisation, the quantification of complexes using ESI-MS, the interpretation of ammonium ion preservation in the complexes in the gas phase, and the use of ion mobility spectrometry to resolve ambiguities regarding the strand stoichiometry, or separate and characterise different structural isomers. We also describe that adding electrospray-compatible organic co-solvents (methanol, ethanol, isopropanol or acetonitrile) to aqueous ammonium acetate increases the stability and rate of formation of dimeric G-quadruplexes, and causes structural transitions to parallel structures. Structural changes were probed by circular dichroism and ion mobility spectrometry, and the excellent correlation between the two techniques validates the use of ion mobility to investigate G-quadruplex folding. We also demonstrate that parallel G-quadruplex structures are easier to preserve in the gas phase than antiparallel structures.

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Section: Introductionmentioning

confidence: 99%

Mass spectrometry and ion mobility spectrometry of G-quadruplexes. A study of solvent effects on dimer formation and structural transitions in the telomeric DNA sequence d(TAGGGTTAGGGT)

Ferreira

Marchand

Gabelica

2012

Methods

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“…The amount of neutralization occurred depends on the size of the DNA, concentration of ammonium ions, and instrument parameters used. [8a, 19] Positively charged dicationic diamidines help in neutralizing the backbone, however, the presence of ligand does not affect the overall charge after forming a complex. For instance, peaks remain the most abundant in -4 and -5 charge states for both free AAATTT and AAATTT + (1) 1 complexes.…”

Section: Discussionmentioning

confidence: 99%

“…Ammonium acetate buffer was used due to its volatility under mass spectrometric conditions. [8a, 9b] DNAs were diluted (5 μ m, 0.15 m ammonium acetate buffer, pH 6.7) with the appropriate concentration of ligand, vortexed, and stored at 4 °C until injection. Ratios with no surrounding punctuations refer to stoichiometry ( i.e .…”

Section: Methodsmentioning

confidence: 99%

“…Electrospray ionization mass spectrometry (ESI-MS) is a powerful method to investigate minor groove binder-DNA complexes. [8] It has been demonstrated that ESI-MS can be used for studying biological macromolecular systems such as DNA complexes because the soft ionization conditions used allow the non-covalent interactions that occur to remain essentially intact. [9] Necessary information such as stoichiometry and relative binding affinities can be determined directly, rapidly, and with little material.…”

Section: Introductionmentioning

confidence: 99%

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Resolution of Mixed Site DNA Complexes with Dimer‐Forming Minor‐Groove Binders by Using Electrospray Ionization Mass Spectrometry: Compound Structure and DNA Sequence Effects

Laughlin

Wang

Kumar

et al. 2015

Chemistry A European J

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Small molecule targeting of the DNA minor groove is a promising approach to modulate genomic processes necessary for normal cellular function. For instance, dicationic diamindines, a well-known class of minor groove binding compounds, have been shown to inhibit interactions of transcription factors binding to genomic DNA. The applications of these compounds could be significantly expanded if we understand sequence-specific recognition of DNA better and could use the information to design more sequence-specific compounds. Aside from polyamides, minor groove binders typically recognize DNA at A-tract or alternating AT base pair sites. Targeting sites with GC base pairs, referred to here as mixed base pair sequences, is much more difficult than those rich in AT base pairs. Compound 1 is the first dicationic diamidine reported to recognize a mixed base pair site. It binds in the minor groove of ATGA sequences as a dimer with positive cooperativity. Due to the well-characterized behavior of 1 with ATGA and AT rich sequences, it provides a paradigm for understanding the elements that are key for recognition of mixed sequence sites. Electrospray ionization mass spectrometry (ESI-MS) is a powerful method to screen DNA complexes formed by analogs of 1 for specific recognition. We also report a novel approach to determine patterns of recognition by 1 for cognate ATGA and ATGA-mutant sequences. We found that functional group modifications and mutating the DNA target site significantly affect binding and stacking, respectively. Both compound conformation and DNA sequence directionality are crucial for recognition.

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“…[13][14][15] However, very scarce information is found in literature about the gas-phase fragmentation of these adducts. In recent years, a couple of fundamental studies started to shed light on the influence of adduct formation on the gas-phase dissociation mechanisms of nucleic acids.…”

Section: Interaction Of Cisplatin With Single-stranded Nucleic Acidsmentioning

confidence: 99%

Elucidation of Nucleic Acid–Drug Interactions by Tandem Mass Spectrometry

Hari¹,

Nyakas²,

Stucki³

et al. 2014

Chimia

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In continuation of the long tradition of mass spectrometric research at the University of Bern, our group focuses on the characterization of nucleic acids as therapeutic agents and as drug targets. This article provides a short overview of our recent work on platinated single-stranded and higher-order nucleic acids. Nearly three decades ago the development of soft ionization techniques opened a whole new chapter in the mass spectrometric analysis of not only nucleic acids themselves, but also their interactions with potential drug candidates. In contrast to modern next generation sequencing approaches, though, the goal of the tandem mass spectrometric investigation of nucleic acids is by no means the complete sequencing of genetic DNA, but rather the characterization of short therapeutic and regulatory oligonucleotides and the elucidation of nucleic acid-drug interactions. The influence of cisplatin binding on the gas-phase dissociation of nucleic acids was studied by the means of electrospray ionization tandem mass spectrometry. Experiments on native and modified DNA and RNA oligomers confirmed guanine base pairs as the preferred platination site and laid the basis for the formulation of a gas-phase fragmentation mechanism of platinated oligonucleotides. The study was extended to double-stranded DNA and DNA quadruplexes. While duplexes are believed to be the main target of cisplatin in vivo, the recently discovered DNA quadruplexes constitute another promising target for anti-tumor drugs owing to their regulatory functions in the cell cycle.

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Evaluation of DNA/Ligand Interactions by Electrospray Ionization Mass Spectrometry

Cited by 42 publications

References 64 publications

Mass spectrometry and ion mobility spectrometry of G-quadruplexes. A study of solvent effects on dimer formation and structural transitions in the telomeric DNA sequence d(TAGGGTTAGGGT)

Mass spectrometry and ion mobility spectrometry of G-quadruplexes. A study of solvent effects on dimer formation and structural transitions in the telomeric DNA sequence d(TAGGGTTAGGGT)

Resolution of Mixed Site DNA Complexes with Dimer‐Forming Minor‐Groove Binders by Using Electrospray Ionization Mass Spectrometry: Compound Structure and DNA Sequence Effects

Elucidation of Nucleic Acid–Drug Interactions by Tandem Mass Spectrometry

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