Ion trap collision-induced dissociation of locked nucleic acids

Huang, Tao; Kharlamova, Anastasia; McLuckey, Scott A.

doi:10.1016/j.jasms.2009.09.020

Cited by 30 publications

(53 citation statements)

References 48 publications

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“…The accurate mass measurements and resolution afforded by mass spectrometry (MS) make this an ideal technique to characterize oligonucleotides [2]. Both matrix-assisted laser desorption/ ionization (MALDI) and electrospray (ESI) MS have been previously applied to determine the sequence of DNA [3][4][5], RNA [6][7][8][9] and oligonucleotides containing base or backbone modifications [1,8,[10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Enhanced In-Source Fragmentation in MALDI-TOF-MS of Oligonucleotides Using 1,5-Diaminonapthalene

Hagan

Smith

Antoine

et al. 2012

J. Am. Soc. Mass Spectrom.

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The capability to rapidly and confidently determine or confirm the sequences of short oligonucleotides, including native and chemically-modified DNA and RNA, is important for a number of fields. While matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometry (MS) has been used previously to sequence short oligonucleotides, the typically low fragmentation efficiency of in-source or post-source decay processes necessitates the accumulation of a large number of spectra, thus limiting the throughput of these methods. Here we introduce a novel matrix, 1,5-diaminonapthalene (DAN), for facile in-source decay (ISD) of DNA and RNA molecular anions, which allows for rapid sequence confirmation. d -, w -, and yseries ions are prominent in the spectra, complementary to the (a-B)-and w -ions that are typically produced by MALDI post-source decay (PSD). Results are shown for several model DNA and RNA oligonucleotides, including combinations of DAN-induced fragmentation with true tandem TOF MS (MS/MS) for pseudo-MS 3 and "activated-ion PSD."

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Section: Introductionmentioning

confidence: 99%

Enhanced In-Source Fragmentation in MALDI-TOF-MS of Oligonucleotides Using 1,5-Diaminonapthalene

Hagan

Smith

Antoine

et al. 2012

J. Am. Soc. Mass Spectrom.

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“…Moreover, some of the synthetic modifications introduced in antisense oligonucleotides are also known to alter the gas-phase dissociation mechanism. While thiophosphate oligonucleotides fragment in a DNA-like manner [11], no preferred dissociation channel was observed for 2'-methoxylated oligonucleotides [12], methylphosphonates [13], or locked nucleic acids [14]. In fact, the fragmentation patterns point towards the coexistence of multiple mechanisms.…”

Section: Ms/ms Of Oligonucleotidesmentioning

confidence: 94%

“…In fact, the fragmentation patterns point towards the coexistence of multiple mechanisms. Recent tandem mass spectrometric studies on LNA [14] and homo-DNA [15] accentuate the impact of the sugar-moiety on the gas-phase dissociation of oligonucleotides. Consequently, understanding the fragmentation of tricyclo-DNA is a key factor for the reliable MS-based sequencing and quantification of the antisense oligonucleotides.…”

Section: Ms/ms Of Oligonucleotidesmentioning

confidence: 99%

The Contribution of the Activation Entropy to the Gas-Phase Stability of Modified Nucleic Acid Duplexes

Hari

Dugovic

Istrate

et al. 2016

J. Am. Soc. Mass Spectrom.

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Abstract. Tricyclo-DNA (tcDNA) is a sugar-modified analogue of DNA currently tested for the treatment of Duchenne muscular dystrophy in an antisense approach. Tandem mass spectrometry plays a key role in modern medical diagnostics and has become a widespread technique for the structure elucidation and quantification of antisense oligonucleotides. Herein, mechanistic aspects of the fragmentation of tcDNA are discussed, which lay the basis for reliable sequencing and quantification of the antisense oligonucleotide. Excellent selectivity of tcDNA for complementary RNA is demonstrated in direct competition experiments. Moreover, the kinetic stability and fragmentation pattern of matched and mismatched tcDNA heteroduplexes were investigated and compared with non-modified DNA and RNA duplexes. Although the separation of the constituting strands is the entropy-favored fragmentation pathway of all nucleic acid duplexes, it was found to be only a minor pathway of tcDNA duplexes. The modified hybrid duplexes preferentially undergo neutral base loss and backbone cleavage. This difference is due to the low activation entropy for the strand dissociation of modified duplexes that arises from the conformational constraint of the tc-sugar-moiety. The low activation entropy results in a relatively high free activation enthalpy for the dissociation comparable to the free activation enthalpy of the alternative reaction pathway, the release of a nucleobase. The gas-phase behavior of tcDNA duplexes illustrates the impact of the activation entropy on the fragmentation kinetics and suggests that tandem mass spectrometric experiments are not suited to determine the relative stability of different types of nucleic acid duplexes.

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“…Abstraction of the 2'-proton and subsequent formation of a cyclic intramolecular transition state induce backbone cleavage at the 5'-C-O bond, thus forming the corresponding c-/y-ion pair. [4,5] Within moiety destabilizes the N-glycosidic bond of the platinated base, thus enhancing backbone cleavage at the 3'-phosphate of the respective nucleotide. [16] 5'-terminal fragments complementary to the high-intensity w-ion include the (a+Pt)-ion as well as the corresponding (unplatinated) (a-B)-ion.…”

Section: Ta Ndem Mass Spectrometry Of Oligonucleotidesmentioning

confidence: 99%

“…While methylphosphonate nucleic acids themselves are of interest for antisense applications, they represent a valuable instrument to study the role of specific phosphate groups in gas-phase recent years, a comprehensive armamentarium of dissociation mechanisms has been assembled, which can be applied to deciphering tandem mass spectrometric data obtained from DNA, RNA, and the many structurally altered oligonucleotide analogues. [6][7][8][9][10][11][12] …”

Section: Ta Ndem Mass Spectrometry Of Oligonucleotidesmentioning

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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Ion trap collision-induced dissociation of locked nucleic acids

Cited by 30 publications

References 48 publications

Enhanced In-Source Fragmentation in MALDI-TOF-MS of Oligonucleotides Using 1,5-Diaminonapthalene

Enhanced In-Source Fragmentation in MALDI-TOF-MS of Oligonucleotides Using 1,5-Diaminonapthalene

The Contribution of the Activation Entropy to the Gas-Phase Stability of Modified Nucleic Acid Duplexes

Elucidation of Nucleic Acid–Drug Interactions by Tandem Mass Spectrometry

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