Mass Spectrometry of Nucleic Acid Noncovalent Complexes

Largy, Eric; König, Alexander; Ghosh, Anirban; Ghosh, Dipankar; Benabou, Sanae; Rosu, Frédéric; Gabelica, Valérie

doi:10.1021/acs.chemrev.1c00386

Cited by 65 publications

(90 citation statements)

References 1,212 publications

(4,013 reference statements)

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“…Our group recently reviewed mass spectrometry of nucleic acid complexes. 19 This more personal account highlights key novel insights generated through our effort in bridging the fields of nucleic acids biophysics and fundamental mass spectrometry. quadruplexes focused on sequences obeying this rule, such as…”

Section: ■ Introductionmentioning

confidence: 99%

“…As a result, in our hands, advances in nucleic acids biophysics have been constantly intertwined with advances in measurement sciences. Our group recently reviewed mass spectrometry of nucleic acid complexes . This more personal account highlights key novel insights generated through our effort in bridging the fields of nucleic acids biophysics and fundamental mass spectrometry.…”

Section: Introductionmentioning

confidence: 99%

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Native Mass Spectrometry and Nucleic Acid G-Quadruplex Biophysics: Advancing Hand in Hand

Gabelica

2021

Acc. Chem. Res.

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Conspectus While studying nucleic acids to reveal the weak interactions responsible for their three-dimensional structure and for their interactions with drugs, we also contributed to the field of biomolecular mass spectrometry, both in terms of fundamental understanding and with new methodological developments. A first goal was to develop mass spectrometry approaches to detect noncovalent interactions between antitumor drugs and their DNA target. Twenty years ago, our attention turned toward specific DNA structures such as the G-quadruplex (a structure formed by guanine-rich strands). Mass spectrometry allows one to discern which molecules interact with one another by measuring the masses of the complexes, and quantify the affinities by measuring their abundance. The most important findings came from unexpected masses. For example, we showed the formation of higher- or lower-order structures by G-quadruplexes used in traditional biophysical assays. We also derived complete thermodynamic and kinetic description of G-quadruplex folding pathways by measuring cation binding, one at a time. Getting quantitative information requires accounting for nonspecific adduct formation and for the response factors of the different molecular forms. With these caveats in mind, the approach is now mature enough for routine biophysical characterization of nucleic acids. A second goal is to obtain more detailed structural information on each of the complexes separated by the mass spectrometer. One such approach is ion mobility spectrometry, and even today the challenge lies in the structural interpretation of the measurements. We showed that, although structures such as G-quadruplexes are well-preserved in the MS conditions, double helices actually get more compact in the gas phase. These major rearrangements forced us to challenge comfortable assumptions. Further work is still needed to generalize how to deduce structures in solution from ion mobility spectrometry data and, in particular, how to account for the electrospray charging mechanisms and for ion internal energy effects. These studies also called for complementary approaches to ion mobility spectrometry. Recently, we applied isotope exchange labeling mass spectrometry to characterize nucleic acid structures for the first time, and we reported the first ever circular dichroism ion spectroscopy measurement on mass-selected trapped ions. Circular dichroism plays a key role in assigning the stacking topology, and our new method now opens the door to characterizing a wide variety of chiral molecules by mass spectrometry. In summary, advanced mass spectrometry approaches to characterize gas-phase structures work well for G-quadruplexes because they are stiffened by inner cations. The next objective will be to generalize these methodologies to a wider range of nucleic acid structures.

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Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Native Mass Spectrometry and Nucleic Acid G-Quadruplex Biophysics: Advancing Hand in Hand

Gabelica

2021

Acc. Chem. Res.

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“…Mass spectrometry analysis of intact polyanionic nucleic acids has nowadays acquired sufficient maturity to be considered as a method of choice for the structural investigation of nucleic acids, including nucleic acids complexed to dendrimers . In particular, ion mobility spectrometry (IMS) experiments represent an invaluable analytical method to generate structural data on gas-phase ions .…”

Section: Introductionmentioning

confidence: 99%

Structural Characterization of Dendriplexes In Vacuo: A Joint Ion Mobility/Molecular Dynamics Investigation

Saintmont

Hoyas

Rosu

et al. 2022

J. Am. Soc. Mass Spectrom.

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The combination between ion mobility mass spectrometry and molecular dynamics simulations is demonstrated for the first time to afford valuable information on structural changes undergone by dendriplexes containing ds-DNA and low-generation dendrimers when transferred from the solution to the gas phase. Dendriplex ions presenting 1:1 and 2:1 stoichiometries are identified using mass spectrometry experiments, and the collision cross sections (CCS) of the 1:1 ions are measured using drift time ion mobility experiments. Structural predictions using Molecular Dynamics (MD) simulations showed that gas-phase relevant structures, i.e., with a good match between the experimental and theoretical CCS, are generated when the global electrospray process is simulated, including the solvent molecule evaporation, rather than abruptly transferring the ions from the solution to the gas phase. The progressive migration of ammonium groups (either NH4 + from the buffer or protonated amines of the dendrimer) into the minor and major grooves of DNA all along the evaporation processes is shown to compact the DNA structure by electrostatic and hydrogen-bond interactions. The subsequent proton transfer from the ammonium (NH4 + or protonated amino groups) to the DNA phosphate groups allows creation of protonated phosphate/phosphate hydrogen bonds within the compact structures. MD simulations showed major structural differences between the dendriplexes in solution and in the gas phase, not only due to the loss of the solvent but also due to the proton transfers and the huge difference between the solution and gas-phase charge states.

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“…The low ionisation efficiency and poor mass spectrometry detection sensitivity of single and double chains of nucleic acids have greatly limited their application [ 14 , 15 ]. In a recent study, DNA detection probes were labelled with rare earth elements; these were hybridised with target DNA chains on magnetic beads, with each element corresponding to different target DNA chains [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Single-Molecule Detection of Nucleic Acids via Liposome Signal Amplification in Mass Spectrometry

Lin

Zhao

et al. 2022

Sensors

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A single-molecule detection method was developed for nucleic acids based on mass spectrometry counting single liposome particles. Before the appearance of symptoms, a negligible amount of nucleic acids and biomarkers for the clinical diagnosis of the disease were already present. However, it is difficult to detect extremely low concentrations of nucleic acids using the current methods. Hence, the establishment of an ultra-sensitive nucleic acid detection technique is urgently needed. Herein, magnetic beads were used to capture target nucleic acids, and liposome particles were employed as mass tags for single-particle measurements. Liposomes were released from magnetic beads via photocatalytic cleavage. Hence, one DNA molecule corresponded to one liposome particle, which could be counted using mass spectrometric measurement. The ultrasensitive detection of DNA (10–18 M) was achieved using this method.

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Mass Spectrometry of Nucleic Acid Noncovalent Complexes

Cited by 65 publications

References 1,212 publications

Native Mass Spectrometry and Nucleic Acid G-Quadruplex Biophysics: Advancing Hand in Hand

Native Mass Spectrometry and Nucleic Acid G-Quadruplex Biophysics: Advancing Hand in Hand

Structural Characterization of Dendriplexes In Vacuo: A Joint Ion Mobility/Molecular Dynamics Investigation

Single-Molecule Detection of Nucleic Acids via Liposome Signal Amplification in Mass Spectrometry

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