Comparison of particle-in-cell simulations with experimentally observed frequency shifts between ions of the same mass-to-charge in fourier transform ion cyclotron resonance mass spectrometry

It has been previously observed that the measured frequency of ions in a Fourier transform mass spectrometry experiment depend upon the number of trapped ions, even for populations consisting exclusively of a single mass-to-charge. Since ions of the same mass-to-charge are thought not to exert a space-charge effect among themselves, the experimental observation of such frequency shifts raises questions about their origin. To determine the source of such experimentally observed frequency shifts, multiparticle ion trajectory simulations have been conducted on monoisotopic populations of Cs⁺ ranging from 10² ions to 10⁶ ions. A close match to experimental behavior is observed. By probing the effect of ion number and orbital radius on the shift in the cyclotron frequency, it is shown that for a monoisotopic population of ions, the frequency shift is caused by the interaction of ions with their image-charge. The addition of ions of a second mass-to-charge to the simulation allows the comparison of the magnitude of the frequency shift resulting from space-charge (ion-ion) effects versus ion interactions with their image charge.     

Toward high pressure miniature protein mass spectrometer: Theory and initial results

Current miniature mass spectrometers mainly focus on the analyses of organic and small biological molecules. In this study, we explored the possibility of developing high resolution miniature ion trap mass spectrometers for whole protein analysis. Theoretical derivation, GPU assisted ion trajectory simulation, and initial experiments on home‐developed “brick” mass spectrometer were carried out. Results show that ion‐neutral collisions have smaller damping effect on large protein ions, and a higher buffer gas pressure should be applied during ion trap operations for protein ions. As a result, higher pressure ion trap operation not only benefits instrument miniaturization, but also improves mass resolution of protein ions. Dynamic mass scan rate and generation of low charge state protein ions are also found to be helpful in terms of improving mass resolutions. Theory and conclusions found in this work are also applicable in the development of benchtop mass spectrometers.     

Space charge effects on relative peak heights in fourier transform-ion cyclotron resonance spectra

Ion trajectory calculations have confirmed that space charge interactions can be a source for mass discrimination seen in Fourier transform-ion cyclotron resonance (FT-ICR) spectra. As compared with the previously recognized mechanism of z-axis excitation, ion-ion repulsion is a mechanism which specifically affects relative peak heights of ions close in mass, and is most severe for low excitation radiofrequency (rf) amplitudes. In this mechanism, Coulomb repulsion significantly perturbs the motion of the ion clouds during excitation and alters the final cyclotron orbital radii. Under these conditions peak heights do not accurately reflect the true ion abundances in the FT-ICR spectrometer. Mass discrimination can be minimized by using low numbers of ions, low ion densities, and a short, high amplitude rf excitation waveform. Experimental observation of the relative peak heights of the m/z 91, 92, and 134 ions in n-butylbenzene gives quantitative confirmation of the results of the trajectory calculations. Chirp, SWIFT, and impulse excitation were modeled: impulse excitation was found to be most effective in minimizing the effects of space charge interactions.     

Comparison of equilibrium ion density distribution and trapping force in penning, Paul, and combined ion traps

Starting from the classical Boltzmann distribution, we obtain the ion density distribution in the limit of either high temperature/low density (Coulomb interaction energy much less than ion kinetic energy) or low temperature/high density (kinetic energy much less than Coulomb interaction energy), and the trapping force for an ion cloud in Penning ion cyclotron resonance, Paul (quadrupole), and combined (Paul trap in a uniform axial static magnetic field) traps. At equilibrium (total angular momentum conserved), the ion cloud rotates at a constant frequency in Penning and combined traps. In a Penning trap, the maximum ion density is proportional to B ²/m (B is magnetic field and m is the mass of ions), whereas the maximum ion density in a Paul trap is proportional to (V _rf ² /mΩ² r ₀ ⁴ ), with Mathieu equation axial q value <0.4 to satisfy the pseudopotential approximation. Ion maximum densities in both Penning and Paul ion traps depend on the trapping field (magnetic or electric) and ion mass, but not on ion charge. In a Penning trap at maximum ion density (zero pressure), the radial (but not the axial) trapping potential is mass dependent, whereas both radial and axial potentials in a Paul trap at maximum ion density are mass dependent.     

Reactions of poly(ethylene glycol) cations with iodide and perfluorocarbon anions

Multiply charged poly(ethylene glycol) ions of the form (M+nNa) ⁿ⁺ derived from electrospray ionization have been subjected to reactions with negative ions in the quadrupole ion trap. Mixtures of multiply charged positive ions ranging in average mass from about 2000 to about 14,000 Da were observed to react with perfluorocarbon anions by either proton transfer or fluoride transfer. Iodide anions reacted with the same positive ions by attachment. In no case was fragmentation of the polymer ion observed. In all cases, the multiply charged positive ion charge states could be readily reduced to +1, thereby eliminating the charge state overlap observed in the normal electrospray mass spectrum. With all three reaction mechanisms, however, the +1 product ions were comprised of mixtures of products with varying numbers of sodium ions, and in the case of iodide attachment and fluoride transfer, varying numbers of halogen anions. These reactions shift the mass distributions to higher masses and broaden the distributions. The extents to which these effects occur are functions of the magnitudes of the initial charges and the width of the initial charge state distributions. Care must be taken in deriving information about the polymer molecular weight distribution from the singly charged product ions arising from these ion/ion reactions. The cluster ions containing iodide were shown to be intermediates in sodium ion transfer. Dissociation of the adduct ions can therefore lead to a +1 product ion population that is comprised predominantly of M+Na⁺ ions. However, a strategy based on the dissociation of the iodide cluster ions is limited by difficulties in dissociating high mass-to-charge ions in the quadrupole ion trap.     

Extending the Dynamic Range of the Ion Trap by Differential Mobility Filtration

A miniature, planar, differential ion mobility spectrometer (DMS) was interfaced to an LCQ classic ion trap to conduct selective ion filtration prior to mass analysis in order to extend the dynamic range of the trap. Space charge effects are known to limit the functional ion storage capacity of ion trap mass analyzers and this, in turn, can affect the quality of the mass spectral data generated. This problem is further exacerbated in the analysis of mixtures where the indiscriminate introduction of matrix ions results in premature trap saturation with non-targeted species, thereby reducing the number of parent ions that may be used to conduct MS/MS experiments for quantitation or other diagnostic studies. We show that conducting differential mobility-based separations prior to mass analysis allows the isolation of targeted analytes from electrosprayed mixtures preventing the indiscriminate introduction of matrix ions and premature trap saturation with analytically unrelated species. Coupling these two analytical techniques is shown to enhance the detection of a targeted drug metabolite from a biological matrix. In its capacity as a selective ion filter, the DMS can improve the analytical performance of analyzers such as quadrupole (3D or linear) and ion cyclotron resonance (FT-ICR) ion traps that depend on ion accumulation.

Observation and implications of high mass-to-charge ratio ions from electrospray ionization mass spectrometry

High mass-to-charge ratio ions (> 4000) from electrospray ionization (ESI) have been observed for several proteins, including bovine cytochrome c (M _r 12,231) and porcine pepsin (M _r 34,584), by using a quadrupole mass spectrometer with an m/z 45,000 range. The ESI mass spectrum for cytochrome c in an aqueous solution gives a charge state distribution that ranges from 12 + to 2 +, with a broad, low-intensity peak in the mass-to-charge ratio region corresponding to the [M + H]⁺ ion. the negative ion ESI mass spectrum for pepsin in 1% acetic acid solution shows a charge state distribution ranging from 7? to 2?. To observe the [M - H]^? ion, harsher desolvation and interface conditions were required. Also observed was the abundant aggregation of the protens with average charge states substantially lower than observed for their monomeric counterparts. The negative ion ESI mass spectrum for cytochrome c in 1–100 mM NH₄OAc solutions showed greater relative abundances for the higher mass-to-charge ratio ions than in acuidic solutions, with an [M - H]^? ion relative abundance approximately 50% that of the most abundant charge state peak. The observation that protein aggregates are formed with charge states comparable to monomeric species (at fower mass-to-charge ratios) suggests that the high mass-to-charge ratio monomers may be formed by the dissociation of aggregate species. The observation of low charge state and aggregate molecular ions concurrently with highly charged species may serve to support a variation of the charged residue model, originally described by Dole and co-workers (Dole, M., et al. J. Chem. Phys. 1968, 49, 2240; Mack, L. L., et al. J. Chem. Phys. 1970, 52, 4977) which involves the Coulombically driven formation of either very highly solvated molecular ions or lower ananometer-diameter droplets.     

Reducing Space Charge Effects in a Linear Ion Trap by Rhombic Ion Excitation and Ejection

Space charge effects play important roles in ion trap operations, which typically limit the ion trapping capacity, dynamic range, mass accuracy, and resolving power of a quadrupole ion trap. In this study, a rhombic ion excitation and ejection method was proposed to minimize space charge effects in a linear ion trap. Instead of applying a single dipolar AC excitation signal, two dipolar AC excitation signals with the same frequency and amplitude but 90° phase difference were applied in the x- and y-directions of the linear ion trap, respectively. As a result, mass selective excited ions would circle around the ion cloud located at the center of the ion trap, rather than go through the ion cloud. In this work, excited ions were then axially ejected and detected, but this rhombic ion excitation method could also be applied to linear ion traps with ion radial ejection capabilities. Experiments show that space charge induced mass resolution degradation and mass shift could be alleviated with this method. For the experimental conditions in this work, space charge induced mass shift could be decreased by ~50%, and the mass resolving power could be improved by ~2 times at the same time.

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Graphical Abstract ?

     

A high performance low magnetic field internal electrospray ionization-fourier transform ion cyclotron resonance mass spectrometer

A new in-magnetic field electrospray ionization (ESI) and Fourier transform ion cyclotron resonance mass spectrometer has been constructed and evaluated. This system is characterized by the use of multiple concentric cryopanels to achieve ultrahigh vacuum in the ion cyclotron resonance cell region, a probe-mounted internal ESI source, and a novel in-field shutter. Initial experiments demonstrate high resolution mass measurement capability at a field strength of 1 T. Mass resolution of 700,000 has been obtained for the 3+ charge state of Met-Lys-bradykinin (at m/z 440) generated by electrospray ionization. When electron impact ionization was employed, resolution in excess of 9,200,000 was achieved for nitrogen molecular ions (N ₂ ⁺ ). Isotopic resolution for molecular ions of bovine ubiquitin (MW=8565 µ) also was achieved by using small ion populations.     

How far can ion trap miniaturization go? Parameter scaling and space‐charge limits for very small cylindrical ion traps

A broad effort is underway to make radiofrequency (RF) ion trap mass spectrometers small enough for portable chemical analysis. A variety of trap geometries and fabrication approaches are under development from several research groups. A common issue is the reduced trapping capacity in smaller traps, with the associated reduction in sensitivity. This article explores the key variables that scale with trap size including RF voltage, frequency, electrical capacitance, power and pseudopotential well depth. High‐field electric breakdown constrains the maximum RF voltages used in smaller ion traps. Simulations show the effects of space charge and the limits of trapping capacity as a function of trap dimensions for cylindrical ion traps down to the micrometer level. RF amplitudes that scale as the1/3, 1/2 and 2/3 power of trap radius, r₀, were studied. At a fixed level of performance, the number of analyzable ions scales as r₀ⁿ, with n ranging from 1.55 to 1.75 depending on the choice of voltage scaling. The implications for miniaturized ion trap mass spectrometry are discussed. Copyright © 2014 John Wiley & Sons, Ltd.     

Of protons or proteins

Mass analyses have been carried out on ions produced by an Electrospray (ES) source from dilute solutions of protein molecules with molecular weights (M) in the range from 5000 to nearly 40000. Each spectrum comprises a sequence of peaks corresponding to multiply charged intact parent species. The ions of each peak differ from those of their adjacent neighbors by one unit charge, H⁺ in these experiments. The maximum number of charges per ion generally increases with the molecular weight of the parent molecule, reaching a value of 45 in the case of alcohol dehydrogenase, atM=39830 the largest species in this study. Thus the resulting values ofm/z are within reach of a simple quadrupole mass filter whose nominal upper mass limit is 1500 daltons! The immediate application for the ES source is in mass spectrometric analysis of large fragile molecules of biochemical importance. But the multiply charged ions it produces are newcomers to the laboratory scene that constitute interesting subjects for study.     

Aspects of recent developments in ion-trap mass spectrometry

Methods which can be used to obtain mass spectra and tandem mass spectra by means of quadrupole ion traps are reviewed and illustrated. High-order (MSⁿ) experiments are described, as is energy-resolved mass spectrometry in which the internal energy deposited upon collision is systematically varied. Ionization methods which can be used in conjunction with ion traps are discussed with special emphasis on experiments in which ions are generated in an external source and injected into the trap for separation and detection. Ion traps are well-suited to on-line monitoring; the performance of membrane probes in these applications is discussed, and detection limits, response times and quantitative accuracy are outlined. Initial attempts to extend the mass range of ion traps have yielded data to more than 45 000 daltons. In addition to being suited to the study of collision-activated dissociation, the experiment on which most applications of tandem mass spectrometry depend, ion traps also allow ion/molecule reactions to be used for these purposes. Use of a pulsed valve to introduce reagent gases in pulses as short as 50 ms facilitates these experiments. Equilibrium conditions are attainable for fast ion/molecule reactions and measurement of equilibrium and rate constants is discussed. Because they combine a range of capabilities, ion traps are well-suited to the study of gaseous ion chemistry, illustrated here by the halomethylation of aromatic compounds, and the competitive dehydration and deamination of α,ω-amino alcohols.     

Structure and Performance of Polygonal Electrode Linear Ion Trap

The polygonal electrode linear ion trap (PeLIT) can produce quadrupolar electric field plus some higher order field, which balances the relationship between mass resolution and electrode manufacturing difficulties. The electrodes of PeLIT are relatively simple, but have a good mass resolving power. This study investigated the relationship between the electric field distribution and the ion trap structures, and the performances of PeLIT through theoretical simulation and experimental study. Research results of simulation showed that the polygonal electrode linear ion traps with different structures had different electric field distributions and mass analysis performances. The negative decapole field distorted the performances significantly. The experimental results showed that the mass resolution of reserpine ions (m/z 609) was more than 2500 using a polygonal electrode ion trap. At the same time, mass selective excitation and tandem mass spectrometry experiments were also carried.     

Space-charge effects with mass-selective axial ejection from a linear quadrupole ion trap

Methods to reduce mass shifts caused by space charge with mass‐selective axial ejection from a linear quadrupole ion trap are investigated. For axial ejection, dipole excitation is applied to excite ions at q ≈ 0.85. The trapping radiofrequency (rf) voltage is scanned to bring ions of different m/z values into resonance for excitation. In the fringing field at the quadrupole exit, excited ions gain axial kinetic energy, overcoming the trapping potential, and are ejected from the trap. Space charge causes the frequencies of ion oscillation to decrease. Thus, greater rf voltages are required to bring ions into resonance for excitation and ejection, and the ions shift to higher apparent masses in a mass spectrum. At the same time, the peaks broaden, lowering resolution. The effects of injection q value, ejection q value, excitation amplitude, quadrupole dc voltages applied to the electrodes, applying an rf voltage to the exit lens, and scan speed, on mass shifts have been studied experimentally. Most experiments were done with only ions of protonated reserpine (m/z 609.3 and its isotopic peaks) in the trap. Some experiments were done with ions of protonated reserpine and ions of m/z 622 in the trap. In general, the mass shifts are reduced with higher ejection q values, higher excitation amplitudes, with quadrupole dc applied, and at higher scan speeds. The application of quadrupole dc appears to increase the ion cloud temperature, which lowers mass shifts. Thus, a proper choice of operating conditions can reduce, but not eliminate, mass shifts caused by space charge. Copyright © 2011 John Wiley & Sons, Ltd.     

Collisional focusing effects in radio frequency quadrupoles

The transmission of ions through a conventional two-dimensional radiofrequency-only (rf) quadrupole has been studied for comparatively high operating pressures between 5 × 10^?4 and 1 × 10^?2 torr. Measurements of signals from mass-resolved analyte ions and total ion currents show that, provided the initial injection ion energy is low (1–30 eV), the ion transmission observed through a small aperture at the exit of the rf quadrupole first increases as the gas pressure increases, reaching a maximum at ? 8 × 10^?3 torr before decreasing at higher pressures. This is in direct contrast to the expectations of classical scattering. This “collisional focusing” appears to be analogous to effects seen in three-dimensional ion traps. The collisional focusing increases with the mass of the ion (not mass-to-charge ratio) for masses up to at least 16,950 u. The collisional focusing of the ions is found to be accompanied by significant losses of axial kinetic energy. A Monte Carlo simulation of the energy loss process is reported that can provide agreement with the observed losses for reasonable collision cross-sections. The results suggest that operation of rf quadrupoles at relatively high pressure may find practical application in sampling ions from high (e.g., atmospheric) pressure ion sources.     

Charge Transfer and Metastable Ion Dissociation of Multiply Charged Molecular Cations Observed by Using Reflectron Time-of-Flight Mass Spectrometry

A multiply charged molecule expands the range of a mass window and is utilized as a precursor to provide rich sequence coverage; however, reflectron time-of-flight mass spectrometer has not been well applied to the product ion analysis of multiply charged precursor ions. Here, we demonstrate that the range of the mass-to-charge ratio of measurable product ions is limited in the cases of multiply charged precursor ions. We choose C₆F₆ as a model molecule to investigate the reactions of multiply charged molecular cations formed in intense femtosecond laser fields. Measurements of the time-of-flight spectrum of C₆F₆ by changing the potential applied to the reflectron, combined with simulation of the ion trajectory, can identify the species detected behind the reflectron as the neutral species and/or ions formed by the collisional charge transfer. Moreover, the metastable ion dissociations of doubly and triply charged C₆F₆ are identified. The detection of product ions in this manner can diminish interference by the precursor ion. Moreover, it does not need precursor ion separation before product ion analysis. These advantages would expand the capability of mass spectrometry to obtain information about metastable ion dissociation of multiply charged species.     

Peak coalescence,spontaneous loss of coherence,and quantification of the relative abundances of two species in the plasma regime: Particle-in-cell modeling of fourier transform ion cyclotron resonance mass spectrometry

Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) is often limited by space-charge effects. Previously, particle-in-cell (PIC) simulations have been used to understand these effects on FTICR-MS signals. However, none have extended fully into the space-charge dominated (plasma) regime. We use a two-dimensional (2-D) electrostatic PIC code, which facilitates work at very high number densities at modest computational cost to study FTICR-MS in the plasma regime. In our simulation, we have observed peak coalescence and the rapid loss of signal coherence, two common experimental problems. This demonstrates that a 2-D model can simulate these effects. The 2-D code can handle a larger numbers of particles and finer spatial resolution than can currently be addressed by 3-D models. The PIC method naturally takes into account image charge and space charge effects in trapped-ion mass spectrometry. We found we can quantify the relative abundances of two closely spaced (such as ⁷Be⁺ and ⁷Li⁺) species in the plasma regime even when their peaks have coalesced. We find that the frequency of the coalesced peak shifts linearly according to the relative abundances of these species. Space charge also affects more widely spaced lines. Singly-ionized ⁷BeH and ⁷Li have two separate peaks in the plasma regime. Both the frequency and peak area vary nonlinearly with their relative abundances. Under some conditions, the signal exhibited a rapid loss of coherence. We found that this is due to a high order diocotron instability growing in the ion cloud.     

Infrared spectroscopy of cold trapped molecular ions using He‐tagging

This review summarizes experimental activities to study the structure of molecular ions via He tagging. The method is based on the attachment of a weakly bound helium atom to a cold ion followed by laser‐induced predissociation (LIP). Since my early involvements (it started in 1977 with a letter from Y.T. Lee), radio frequency (rf) ion traps and ion guides have been important elements in instruments dedicated to ion spectroscopy. Accumulating ions in a ring electrode trap (RET) and confining them together with the laser‐induced photofragments in a long octopole has been demonstrated in 1978 in Berkeley via photodissociation of metastable O₂⁺ ions. In the early stage of this instrument, as well as in various further developments, supersonic expansions have been used to create weakly bound complexes. An important step forward for ion spectroscopy was to push the conditions of cryogenic ion traps so far that, finally, He atoms could be attached to almost any mass‐selected ion of interest, including multiply charged ions and C₆₀⁺. Currently, modern ion storage instruments reach temperatures below 3 K and can be operated at helium densities above 10¹⁶ cm⁻³, opening up many avenues of application in spectroscopy, reaction dynamics, and analytical chemistry. In addition to a personal historical review, I discuss recent progress made with new cryogenic ion traps, especially in the field of He tagging. He‐M⁺ ions have been formed via ternary association for all kind of M⁺ ions ranging from atoms such as He⁺, N⁺, or Fe⁺ via molecules N₂⁺, VO⁺, and H₃⁺ to various polyatomic ions. The in situ synthesis of tagged ions made unique discoveries possible, such as determining the structure of doubly charged benzene, the first identification of a carrier of diffuse interstellar bands, or the characterization of the fundamental 4 electron 4 center system He–H₃⁺. In the conclusions, hints to additional applications will be given, emphasizing on the versatility of temperature‐variable ion traps.     

Equilibrium space charge distribution in a quadrupole ion trap

A simple model provides a basis for evaluating the ion spatial distribution in a uadrupole (Paul) ion trap and its effect on the total potential (trap potential plus space charge 3 acting on ions in the trap. By combining the pseudopotential approximation introduced by Dehmelt 25 years ago with the assumption of thermal equilibrium (leading to a Boltzmann ion energy distribution), the resulting ion spatial distribution (for ions of a single mass-to-charge ratio) depends only on total number of ions, trap pseudopotential, and temperature. (The equilibrium assumption is justified by the high helium bath gas pressure at which analytical quadrupole ion traps are typically operated.) The electric potential generated by the ion space charge may be generated from Poisson’s equation subject to a Boltzmann ion energy distribution. However, because the ion distribution depends in turn on the total potential, solving for the potential and the ion distribution is no longer a simple boundary condition differential equation problem; an iterative procedure is required to obtain a self-consistent result. For the particularly convenient operating condition, (a _z = -8qU/m? ₀ ² Ω², and q _z =-4qV m? ₀ ² Ω², where U and V are direct current and radiofrequency (frequency, ω) voltages applied to the trap, m/q is ion mass-to-charge ratio, and ?₀ is the radius of the ring electrode at the z=0 midplane], both the pseudopotential and the ion distribution become spherically symmetric. The resulting one-dimensional problem may be solved by a simple optimization procedure. The present model accounts qualitatively for the dependence of total potential and ion distribution on number of ions (higher ion density or lower temperature flattens the total potential and widens the spatial distribution of ions) and pseudopotential (higher pseudopotential increases ion density near the center of the trap without widening the ion spatial distribution).