Structural elucidation and isomeric differentiation/quantitation of monophosphorylated phosphoinositides using gas-phase ion/ion reactions and dissociation kinetics

Fabijanczuk, Kimberly; Chao, Hsi‐Chun; Fischer, Joshua L.; McLuckey, Scott A.

doi:10.1039/d2an00792d

Cited by 6 publications

(12 citation statements)

References 39 publications

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“…To explore this possibility, we applied dipolar DC (DDC) collisional activation, a broadband activation technique. We have previously reported various implementations of DDC. ,,, It has been demonstrated that by changing the applied time of DDC while keeping the voltage constant, pseudo-first-order kinetics are observed, and thus, dissociation rates can be determined. Dissociation rate determination has been able to offer fundamental insights into topics such as gas-phase covalent bond formation energetics, , determining effective ion temperatures, and lipid isomeric differentiation .…”

Section: Resultsmentioning

confidence: 99%

“…We have previously reported using divalent alkaline earth metals complexed with tris 1,10-phenanthroline (phen) − and 2,2′:6′,2″-terpyridine (terpy) − to charge-invert singly charged lipid species that allowed for in-depth structural characterization and isomeric differentiation. However, larger lipids such as Lipid A, cardiolipin, and phosphatidylinositol phosphate , preferentially ionize as dianions, precluding divalent metal complexes as suitable reagents for ion/ion reactions due to inevitable neutralization.…”

Section: Introductionmentioning

confidence: 99%

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Charge Inversion of Mono- and Dianions to Cations via Triply Charged Metal Complexes: Application to Lipid Mixtures

Fabijanczuk,

Foreman,

McLuckey

2023

Anal. Chem.

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Electrospray ionization (ESI) of mixtures can give rise to ions with different masses and charges with overlapping massto-charge (m/z) ratios. Such a scenario can be particularly problematic for the detection of low-abundance species in the presence of more highly abundant mixture components. For example, negative mode ESI of polar lipid extracts can result in highly abundant singly charged glyerophospholipids (GPLs), such as phosphatidylethanolamines (PE) and phosphatidylglycerols (PG), that can obscure much less abundant cardiolipins (CLs), which are complex phospholipids with masses roughly double those of GPLs that mostly form doubly charged anions. Despite their low relative abundance, CLs are lipidome components that perform vital biological functions. To facilitate the study of CLs in lipid mixtures without resorting to offline or online separations, we have developed a gas-phase approach employing ion/ion reactions to charge invert anionic lipid species using a trivalent metal-complex. Specifically, ytterbium(III) is shown to readily complex with three neutral ligands, N,N,N′,N′-tetra-2-ethylhexyl diglycolamide (TEHDGA), to form [Yb(TEHDGA 3 )] 3+ using ESI. Herein, we describe pilot studies to evaluate [Yb(TEHDGA) 3 ] 3+ as an ion/ion reagent to allow for chemical separation of doubly and singly charged anions, using lipid mixtures as examples, without neutralizing ions of either charge state.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Charge Inversion of Mono- and Dianions to Cations via Triply Charged Metal Complexes: Application to Lipid Mixtures

Fabijanczuk,

Foreman,

McLuckey

2023

Anal. Chem.

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“…Unlike single-frequency IT-CID, both precursor and product ions experience RF heating, which leads to sequential fragmentation, particularly at long DDC-CID times. For the measurement of the fragmentation rate of a precursor ion, DDC-CID is preferred because it is much less tuning-sensitive relative to single-frequency IT-CID. , In the DDC experiment presented here, ions are isolated in Q1 and stored in q2, where they are collisionally cooled for 0.04 s. DDC-CID is then applied to q2 for a specified range between 0.05 and 0.7 s for this experiment. Ions are then cooled again for 0.03 s before being sent to the detector for 0.13 s.…”

Section: Methodsmentioning

confidence: 99%

“…Dissociation rates under DDC-CID activation conditions follow pseudo-first-order kinetics, – as indicated in eq . false[ M false] t = e − k diss t false[ M false] t = P t × A P t + F t , goodbreak0em2em⁣ where .25em A = TI C t TI C 0.05 where [ M ] t is the mole fraction or survival yield of the precursor ion at time t , k diss is the dissociation rate, and TIC is the total ion count. The survival yield (eq ) is determined by dividing the residual precursor signal by the sum of the residual precursor signal ( P t ) and all identified product ions ( F t ).…”

Section: Methodsmentioning

confidence: 99%

Gas-Phase Fragmentation as a Probe of G-Quadruplex Formation

Brundridge,

Dickerhoff,

Yang

et al. 2023

Anal. Chem.

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G-quadruplex (G4) DNA is found in oncogene promoters and human telomeres and is an attractive anticancer target. Stable G4 structures form in guanine-rich sequences in the presence of metal cations and can stabilize further with specific ligand adduction. To explore the preservation and stability of this secondary structure with mass spectrometry, gas-phase collision-induced dissociation kinetics of G4-like and non-G4-like ion structures were determined in a linear quadrupole ion trap. This study focused on a sequence from the promoter of the MYC oncogene, MycG4, and a mutant non-G4-forming sequence, MycNonG4. At relatively high ion activation energies, the backbone fragmentation patterns of the MycG4 and MycNonG4 are similar, while potassium ion-stabilized G4-folded [MycG4 + 2K-7H]5– and counterpart [MycG4-5H]5– ions are essentially indistinguishable, indicating that high-energy fragmentation is not sensitive to the G4 structure. At low energies, the backbone fragmentation patterns of MycG4 and MycNonG4 are significantly different. For MycG4, fragmentation over time differed significantly between the potassium-bound and free structures, reflecting the preservation of the G4 structure in the gas phase. Kinetic measurements revealed the [MycG4 + 2K-7H]5– ions to fragment two to three times more slowly than the [MycG4-5H]5–. Results for the control MycNonG4 indicated that the phenomena noted for [MycG4 + 2K-7H]5– ions are specific to G4-folding. Therefore, our data show that gentle activation conditions can lead to fragmentation behavior that is sensitive to G-quadruplex structure, revealing differences in kinetic stabilities of isomeric structures as well as the regions of the sequence that are directly involved in forming these structures.

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“…Tandem mass spectrometry is widely employed for the primary structural characterization of polyatomic ions via dissociation reactions induced by one or more dissociation methods. − Structural information is usually inferred from the identities of the product ions. However, under appropriate conditions, dissociation kinetics can be useful in distinguishing isomeric ions that yield the same product ions and can reveal both energetic and dynamic information about dissociation pathways . Slow heating methods, including both collision- and light-mediated energy transfers, lend themselves particularly well to the measurement of dissociation kinetics in ion trapping instruments.…”

Section: Introductionmentioning

confidence: 99%

Dissociation Kinetics in Quadrupole Ion Traps: Effective Temperatures under Dipolar DC Collisional Activation Conditions

Mehnert

Fischer

McDaniel

et al. 2023

J. Am. Soc. Mass Spectrom.

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Ions stored in an electrodynamic ion trap can be forced from the center of the ion trap to regions of higher radio frequency (RF) electric fields by exposing them to a dipolar DC (DDC) potential applied across opposing electrodes. Such ions absorb power from the trapping RF field, resulting in increased ripple motion at the frequency of the trapping RF. When a bath gas is present, ions undergo energetic collisions that result in “RF-heating” sufficient to induce fragmentation. DDC is therefore a broad-band (i.e., mass-to-charge-independent) means for collisional activation in ion traps with added bath gas. Under appropriate conditions, the internal energy distribution of an ion population undergoing dissociation can be approximated with an effective temperature, Teff. In such cases, it is possible to determine thermal activation parameters, such as Arrhenius activation energies and A-factors, by measuring dissociation kinetics. In this work, the well-studied thermometer ion, protonated leucine enkephalin, was subjected to DDC activation under rapid energy exchange conditions and in two separate bath gases, N2 and Ar, to measure Teff as a function of the ratio of DDC and RF voltages. As a result, an empirically derived calibration was generated to link experimental conditions to Teff. It was also possible to quantitatively evaluate a model described by Tolmachev et al. that can be used to predict Teff. It was found that the model, which was derived under the assumption of an atomic bath gas, accurately predicts Teff when Ar was used as the bath gas but overestimates Teff when N2 was the bath gas. Adjustment of the Tolmachev et al. model for a diatomic gas resulted in an underestimate of Teff. Thus, use of an atomic gas can provide accurate activation parameters, while an empirical correction factor should be used to generate activation parameters using N2.

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Structural elucidation and isomeric differentiation/quantitation of monophosphorylated phosphoinositides using gas-phase ion/ion reactions and dissociation kinetics

Abstract: Phosphoinositides, phosphorylated derivatives of phosphatidylinositols, are essential signaling phospholipids in all mammalian’s cellular membranes. With three known phosphorylated derivatives of phosphatidylinositols at the 3-, 4-, and 5- positions along the...

Cited by 6 publications

References 39 publications

Charge Inversion of Mono- and Dianions to Cations via Triply Charged Metal Complexes: Application to Lipid Mixtures

Charge Inversion of Mono- and Dianions to Cations via Triply Charged Metal Complexes: Application to Lipid Mixtures

Gas-Phase Fragmentation as a Probe of G-Quadruplex Formation

Dissociation Kinetics in Quadrupole Ion Traps: Effective Temperatures under Dipolar DC Collisional Activation Conditions

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