Mass Selective Ion Transfer and Accumulation in Ion Trap Arrays

Sep 24, 2014 - Yuan Tian , Trevor K. Decker , Joshua S. McClellan , Linsey Bennett , Ailin Li , Abraham De la Cruz , Derek Andrews , Stephen A. Lammer...
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Mass Selective Ion Transfer and Accumulation in Ion Trap Arrays Yuzhuo Wang,†,∥ Xiaohua Zhang,‡,∥ Yanbing Zhai,† You Jiang,§ Xiang Fang,§ Mingfei Zhou,‡ Yulin Deng,† and Wei Xu*,† †

School of Life Science, Beijing Institute of Technology, Beijing 100081, China Department of Chemistry, FUDAN University, Shanghai 200433, China § National Institute of Metrology, Beijing 100013, China ‡

S Supporting Information *

ABSTRACT: The concept and method for mass selective ion transfer and accumulation within quadrupole ion trap arrays have been demonstrated. Proofof-concept experiments have been performed on two sets of ion trap arrays: (1) a linear ion trap with axial ion ejection plus a linear ion trap with radial ion ejection; (2) a linear ion trap with axial ion ejection plus a linear ion trap with axial ion ejection. In both sets of ion trap arrays, ions trapped in the first ion trap could be mass selectively transferred and accumulated into the second ion trap, while keeping other ions reserved in the first ion trap. Different operating modes have been implemented and tested, including transferring all ions, ions within a selected mass range, ions with a mass-to-charge ratio of 1, and randomly selected ions. Unit mass resolution for ion transfer and ∼90% ion transfer efficiency has been achieved. A new tandem mass spectrometry scheme for analyzing multiple precursor ions in a single sample injection has been demonstrated, which would improve instrument duty cycle and sample utilization rate (especially for very limited samples), potentially facilitate applications like single cell analyses, and improve electron transfer dissociation efficiency.

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Mass selective ion transfer and accumulation within mass analyzer arrays could be useful in many applications, such as extending the sensitivity and dynamic range for low abundant ions, monitoring intermediate or active products in gas-phase ion reactions, and so forth. As a mass analyzer, a quadrupole ion trap has the ability of mass selective ion ejection; however, it remains challenging to implement mass selective ion transfer and accumulation within mass analyzer arrays. Ion transfer and accumulation have been demonstrated between 3D ion traps to enhance ion signal, however without mass selective capability.31−33 Two types of linear ion traps have been used to transfer ions: (1) linear ion trap with hyperbolic electrodes and radial ion ejection capability;4 (2) linear ion trap with round electrodes and axial ion ejection capability.3,34 During mass selective radial ion ejection, ions are ejected from the ejection slits (for instance, 20 to 40 mm long, 0.5 to 1 mm wide) with a broad kinetic energy distribution (typically 0 to 200 eV), so it is very hard for the consecutive device to collect or accumulate ejected ions. In the LTQ Velos type of commercial instruments with dual linear ion trap designs,35 ions could be transferred from ion trap number one (working at high buffer gas pressure ∼4.7 mTorr) to ion trap number two (working at low buffer gas pressure ∼0.35 mTorr). However, there is no mass selectivity at all for the ion transfer process, and multiple DC voltages were applied to carefully move all ions from trap number one to trap number two.28 With the

uadrupole ion traps have been widely used in mass spectrometry (MS) systems due to their capabilities of trapping ions and performing tandem mass spectrometry (MSn).1,2 Although ion trapping capacity has been increased with the development of linear ion traps,3,4 performance of a single ion trap is still limited by duty cycle and mass resolution. To overcome these limitations, quadrupole ion traps have been used in the form of ion trap arrays5−7 and/or integrated with other mass analyzers, including time-of-flight (TOF) mass analyzers,6−10 Fourier transform ion cyclotron resonance (FTICR) cells11,12 and Orbitraps.13,14 Duty cycle,6,15−18 sensitivity,4,11,12,19,20 mass resolution,19,21 and gas-phase ion analysis22,23 capabilities of hybrid instruments are greatly improved through the combination of quadrupole ion traps with other mass analyzers.24,25 The ability to transfer ions from a quadrupole ion trap to another mass analyzer is one of the most important factors in a hybrid instrument. A quadrupole ion trap is typically placed before other mass analyzers for collecting ions, minimizing space charge problems by ejecting unwanted ions, and/or adding MSn capabilities to the system.26−28 Ions processed in the quadrupole ion trap need to be transferred to subsequent devices for further analysis. When coupled with other quadrupole ion traps or FTICR cells, ions are typically carefully ejected out of the quadrupole ion trap with controlled kinetic energies.26,29 On the other hand, ions are normally pulsed out of the quadrupole ion trap with high kinetic energies when combined with TOF8−10,30 or Orbitraps.13 In both cases, there is no mass selectivity for the ion transfer process between mass analyzers. © 2014 American Chemical Society

Received: June 6, 2014 Accepted: September 24, 2014 Published: September 24, 2014 10164

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Figure 1. Schematic of the experimental platform. Bottom left: picture of the first set of ion trap array: LIT1 + LIT2; Bottom right: picture of the second set of ion trap array LIT1 + LIT3.

the ion trap array. The length, rod radius and field radius of the quadrupole ion guide (or quadrupole rods) are 131, 6, and 5.33 mm, respectively. Ion Trap Arrays. Two sets of ion trap arrays have been constructed and tested in the experiments. The first set of ion trap array consists of a linear ion trap with circular electrodes (or rods, namely LIT1) and a linear ion trap with hyperbolic electrodes (namely, LIT2) as shown in Figure 1. Dimensions of LIT1 are the following: length, 131 mm; rod radius, 6 mm; field radius, 5.33 mm. Two circular plate electrodes (thickness: 1 mm, radius: 20 mm) were placed at both ends of the quadrupole rods to serve as the end-cap electrodes. There is a hole (inner radius ∼2 mm) on each end-cap for ion injection and ejection. These end-caps were placed ∼3.5 mm away from the quadrupole rods. LIT2 has the following dimensions: center to electrode distance 4 mm in both x- and y-directions; length in z-direction 40 mm. Each hyperbolic electrode has an ejection slit (width: 0.5 mm, length: 20 mm). With an end-cap electrode placed at the backside (thickness: 1 mm, hole radius, 2 mm), LIT2 is sharing an end-cap electrode with LIT1 as the front end-cap. In this setup, two electron multipliers, one at the backend and one at the side of LIT2, were used for ion detection. The second set of ion trap array consists of two linear ion traps (LIT1 and LIT3) both with circular electrodes as shown in Figure 1. The same ion trap, LIT1was used in both sets of ion trap arrays as the first ion trap. Sealed by a cylindrical sleeve, the second ion trap in this case (LIT3) has the following dimensions: length, 131 mm; rod radius, 6 mm; field radius, 5.33 mm. In this setup, a single ion detector was placed at the backend of LIT3. Electronic Control System. An electronic control system was developed in-house. Two dual-phase radio frequency (rf) signals and two alternative current (AC) signals (with stored waveform inverse Fourier transform function, SWIFT) were generated to control the two linear ion traps in the ion trap arrays. Through capacitive coupling, the rf signal applied on the first ion trap (LIT1) was also used to drive the quadrupole ion guide. Three high direct current (DC) voltages (−2 to 0 kV, −2 to 0 kV, −10 to 10 kV) were generated to provide the high

axial ion ejection, space charge effects were decreased with a tandem ion trap array design, in which the first ion trap was used as the accumulation trap and the second ion trap was used as the analyzer trap.27 In this study, methods for mass selective transfer and accumulation were proposed and realized on two sets of ion trap arrays. Two linear ion traps were used in both sets of ion trap arrays. With axial ion ejection capability, the first linear ion trap (with round electrodes) could be used for ion trapping, reactions, or analysis. . The second linear ion trap was used as the ion accumulator and analyzer, which serves to accumulate ions ejected from the first ion trap and analyze them. Two linear ion traps have been tested as the second linear ion trap, including a linear ion trap with hyperbolic electrodes and radial ion ejection capability; a linear ion trap with round electrodes and axial ion ejection capability. Resolution and accumulation efficiency of the mass selective ion transfer process were characterized for both setups. Different ion transfer modes have been explored. With this new method, tandem MS for multiple precursor ions could be performed in a single sample injection. This could be potentially useful in applications where samples are very limited, such as in the analyses of a single cell36−38 or a spatial spot during MS imaging.39,40

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EXPERIMENTAL SECTION

A new experimental platform was set up in lab for implementing this mass selective ion transfer and accumulation method. Figure1 is a schematic of the MS system, which mainly includes a nano-ESI source, a quadrupole ion guide, anion trap array, a vacuum system, and an electronic control system. Vacuum System. A three-stage vacuum chamber with continuous inlet was constructed, and the pressures within each stage are 1 Torr, 1 mTorr and 0.04 mTorr, respectively, which were maintained by two turbo-molecular pumps (Hipace300, Pfeiffer Vacuum, Germany) and one mechanical pump (E2M28, Edwards, England). In addition, the pressure in ion trap No. 2 was maintained at ∼1 mTorr by introducing N2 as the buffer gas. A quadrupole ion guide was used to guide ions into 10165

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Figure 2. Different ion transfer modes in the first set of ion trap array with LIT1 + LIT2. The first ion transfer mode: (a) PEG ions trapped in LIT1, (b) ions transferred from LIT1 and trapped in LIT2. The second ion transfer mode: (c) ions left in LIT1, (d) ions transferred and trapped in LIT2. The third ion transfer mode: (e) ions left in LIT1, (f) ions transferred and trapped in LIT2. The fourth ion transfer mode: (g) ions left in LIT1, (h) ions transferred and trapped in LIT2. See text for details.

methanol/water (1:1 v/v) to 100 μg/mL, 100 μg/mL, 50 μg/ mL, 50 μg/mL, and 0.1 μg/mL, respectively.

voltages for ion detectors, including a dynode. DC signals on the end-caps and skimmers were also provided by the electronic control system. Samples. Polyethylene glycol (PEG), reserpine, atenolol, vitamin B1, and angiotensin II were purchased from SigmaAldrich (St. Louis, MO, U.S.A.). Electro-sprayed PEG, reserpine, atenolol, vitamin B1, and angiotensin II were diluted with

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RESULTS AND DISCUSSION

To achieve mass selective ion transfer and accumulation, the first ion trap (LIT1) in the ion trap array needs to mass selectively eject ions. Furthermore, the second ion trap (LIT2 or LIT3) 10166

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Figure 3. Ion transfer in the second set of ion trap array with LIT1 + LIT3 using the third ion transfer mode (see text for details): (a) reserpine ions trapped in LIT1; (b) ions left in LIT1 after ion transfer; (c) ions transferred and trapped in LIT3.

should be able to capture and accumulate ions ejected from LIT1. In the experiments, ions generated by the nano-ESI source were first transferred and trapped in ion trap No. 1. During ion trapping, the DC voltage on the end-cap electrode between ion trap No. 1 and No. 2 was set at ∼80 V. With axial ion ejection, ions of interest will be excited in the x-direction using a dipolar AC (∼1.5 V, ∼115 kHz). Ion motions in x, y, and z-directions will be mixed by the fringing field near the trap exit.3,41 With enough kinetic energies, ions will overcome the DC barrier set by the end-cap (∼5 V) and be ejected along the z-direction of LIT1 toward the second ion trap. A relatively low pressure was kept in LIT1 (∼0.04 mTorr) to avoid collision induced dissociation (CID) of excited ions. The second ion trap then needs to trap the incoming ions. To that end, the pressure in LIT2 and LIT3 was kept at ∼1 mTorr, so that excess kinetic energy of ions could be removed through ion-neutral collisions. Different Ion Transfer Modes. Mass selective ion transfer between ion traps could be achieved in many different fashions using both sets of ion trap arrays. As a demonstration, Figure 2 shows four different ion transfer modes using LIT1 and LIT2 in the ion trap array. In Figure 2a, PEG ions were trapped in LIT1, then axially ejected and detected by the detector placed at the backend of LIT2. During this process, LIT2 was used as an ion guide with a constant rf voltage applied (∼170 V0‑p). PEG ions trapped in LIT1 could be transferred to LIT2. Figure 2b shows the case where all PEG ions were transferred to LIT2. In this process, ions were mass selectively scanned by dipolar resonance ejection (rf voltage on LIT1 scanned while applying a dipolar AC signal on x-electrodes of LIT1, ∼1.5 V0‑p and 310 kHz). Ions were collected in LIT2, then radially ejected and detected by the detector placed at the side of LIT2. Detailed scan functions could be found in Supporting Information. In the second ion transfer mode, ions within a selected mass range could be transferred and accumulated in LIT2, as shown in Figure 2c,d. Ions with m/z ratios between ∼603−667 Da were transferred from LIT1 to LIT2. Figure 2c plots the mass spectrum collected from LIT1 after ion transfer, which demonstrates that ions with m/z ratios between ∼603−667 Da were ejected from LIT1. Ejected ions were then trapped in LIT2 as shown in Figure 2d. In this experiment, dipolar resonance ejection was also applied on LIT1 (see Supporting Information for scan function). In the third ion transfer mode, ions with a selected m/z ratio was transferred and collected in LIT2. In this mode, a fixed rf voltage and a fixed dipolar AC signal were applied on LIT1, so that the secular motion frequency of the selected ion (m/z 613 Da) would be the same as that of the dipolar AC signal. Different form rf scan methods, ions could be continuously transferred

from LIT1 to LIT2 as soon as selected ions were generated or introduced in LIT1, which might be useful in the protection and detection of intermediate product ions during gas-phase ion reaction experiments. In the fourth ion transfer mode, multiple randomly selected ions could be transferred from LIT1 to LIT2. As an example, ions with m/z 613 and 657 Da were selected for transfer. A fixed dipolar AC signal (∼1.5 V0‑p and ∼113 kHz) was applied on the x-electrodes of LIT1, and the rf voltage was first set at ∼235 V0‑p for 50 msto transfer ions with m/z 613 Da. The rf voltage was then elevated to ∼251 V0‑p for 50 ms to transfer ions with m/z 657 Da. As plotted in Figure 2g,h, ions with m/z 613 and 657 Da were transferred and collected in LIT2, while keeping all other ions (including ions with m/z 635 Da) trapped in LIT1. Instead of tuning the rf voltage, frequency of the dipolar AC signal could also be adjusted for selected ion ejection, as well as applying a broadband AC signal with multiple frequency components. In all these transfer processes, no SWIFT (stored waveform inverse Fourier Transform) waveform has been applied. Resolution for the mass selective ion transfer is equal to ion ejection resolution of LIT1 when using the axial ion ejection method. As shown in Figure 2, the mass resolution of LIT1 is not high. The main reason for the relatively low resolution is believed to be the fringing field at the exit of LIT1 was affected by the electric field in LIT2. The geometry and dimension of LIT2 are different from those of LIT1, so that the electric field distribution in LIT2 would be different from that in LIT1. Because the hole on the end-cap between LIT1 and LIT2 has a relatively large inner diameter (4 mm), the rf electric field in LIT2 will be coupled into LIT1. Therefore, the disturbed fringing field in LIT1 would result in lower mass resolution. Resolution of the mass selective ion transfer was improved by using the second set of ion trap array, which consists of LIT1 and LIT3. Because the field diameter and electrode geometry of LIT3 are the same as those of LIT1, distortion of the fringing field in LIT1 by LIT3 would be minimized. Mass resolution of the ion transfer process directly relates to the dipolar resonance ejection process in LIT1. After optimization of the rf scan speed(2595 Da/s), AC frequency and amplitude(355 kHz, 1.6 V0‑p) as done by Hager,3 the mass resolution of LIT1 was improved. Using the same ion axial ejection method on LIT1, isotope peaks of reserpine (m/z 609 Da, 610 and 611 Da) could be observed well in the mass spectrum. With the improved mass resolution (fwhm 0.12, at 610 Da), the ion transfer resolution could also be increased. As a demonstration shown in Figure 3b,c, ions with m/ z 610 Da were transferred into LIT3 using the third ion transfer mode as discussed earlier. After ion transfer, ions with m/z 609 10167

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Figure 4. Tandem MS for multiple precursor ions in a single sample injection. (a) Ion current of angiotensin II from paper spray ionization (solution loading volume: 5 μL); (b) mass spectrum of vitamin B1,atenolol, and reserpine mixture from LIT1; (c) scan function for the tandem MS. (RF1, AC1: the rf and AC signals applied on LIT1; RF2, AC2: the rf and AC applied on LIT2; DC1: DC voltage applied on the left end-cap of LIT1; DC2: DC voltage applied on the end-cap between LIT1 and LIT2; DC3: DC voltage applied on the right end-cap of LIT2) (d−f) Tandem mass spectra for vitamin B1, atenolol, and reserpine, respectively.

and 611 Da could be well preserved in LIT1 as shown in Figure 3b. Tandem MS for Multiple Precursor Ions in a Single Sample Injection. Coupled with chromatography techniques, modern MS systems have been widely used in complex sample analysis, such as in proteomics, metabolomics, among other techniques.42 In both data-dependent acquisition (DDA)43,44 and data-independent acquisition (DIA)45,46 strategies, analysis speed or duty cycle of MS scan, especially tandem MS scan is critical to improve the coverage of analytes. With mass selective ion transfer and accumulation capability, an ion trap array could be used to perform tandem MS for multiple precursor ions in a single sample injection. This technique could be used for ionization techniques or sample conditions in which a flux of ions is only provided once (or for very limited durations), for example, in matrix-assisted laser desorption ionization (MALDI) or desorption electrospray ionization (DESI) imaging of a tissue sample spot,47 and paper spray ionization.48 A proof-of-concept experiment was carried out with the first set of ion trap array and using paper spray as the ionization method. When paper spray ionization was used to generate ions from a sample, the ion current would typically last for several seconds with ion intensity varies with time as shown in Figure 4a. Similar to the case in LC-MS, the short ion current duration with varied ion intensity limits the number of precursor ions that could be analyzed. With the mass spectrum shown in Figure 4b, a mixture of vitamin B1, atenolol, and reserpine was electro-sprayed by paper spray and trapped in LIT1. Vitamin B1 ions were first mass selectively transferred to LIT2 and fragmented in LIT2 using CID. A MS scan was then performed in LIT2 to get the tandem mass spectrum for vitamin B1, as plotted in Figure 4d. After that, the same operation was carried

out one by one for atenolol and reserpine, with the tandem mass spectra shown in Figure 4e,f. Figure 4c shows the scan function for the whole process. The scan speed of a mass spectrometry system could also be improved with this multiple precursor analysis methodology, when the ion injection plus cooling duration (and prescan if necessary) is comparable with the ion dissociation plus mass analysis duration.32 As shown earlier, three tandem mass spectra were successively obtained with a single ion introduction. Conventionally, ions need to be reintroduced again when analyzing different precursor ions. Therefore, ion introduction and cooling periods could be saved in the proposed method. For example, if five peaks in a mass spectrum were chosen to perform tandem MS analyses. Assume: 50 ms for the ion introduction and cooling periods during each scan; 50 ms for the CID and MS scan. With the conventional method, a total of 0.5 s ((50 ms +50 ms) × 5) is needed to obtain the five tandem mass spectra. With the proposed method, the same analyses could be finished in 0.3 s (50 ms + 50 ms × 5), where the scan speed was increased by ∼1.6 times. More time could be saved when more precursor ions need to be analyzed, and the total time (t) that could be saved is t = (N − 1) × T

(1)

where N is the number of precursor ions need to be analyzed, and T is the time needed for ion introduction and cooling. Mass Selective Ion Accumulation. The ion accumulation capability would enhance the sensitivity of a MS system, especially for the detection of low-abundant ions.31,32 In the ion trap arrays developed in this work, ions of interest in LIT1could be mass selectively transferred and accumulated in the second ion trap (LIT2 or LIT3). Both sets of ion trap arrays were tested, and the second ion transfer mode was used. PEG 10168

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Figure 5. Mass selective ion accumulation: (a) ion accumulation efficiency in the first set of ion trap array (LIT1+LIT2); (b) ion accumulation efficiency in the second set of ion trap array (LIT1+LIT3); (c) scan function for three-time ion accumulation.

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ions from the nano-ESI source were injected into LIT1 for three times, and during each time, ions with m/z 613 Da were transferred and accumulated in the second ion trap (scan function shown in Figure 5c). In both setups, ions were detected using the same electron multiplier, which was placed on the backend of the second ion trap. Ion transfer efficiency was calculated as the ratio of the area of selected mass peak collected from the second ion trap over that collected from ion trap No. 1. (see Supporting Information for details) With the first set of ion trap array (LIT1+LIT2), the ion transfer efficiency is relatively low (∼12.5%), as shown in Figure 5a. With the second set of ion trap array (LIT1+LIT3), an ion transfer efficiency of ∼91.50% and an ion accumulation efficiency (accumulated 3 times) of 222.09% could be achieved (see Figure 5b). The second set of ion trap array has higher ion accumulation efficiency, because LIT3 is much longer than LIT2. In LIT3, more ion-neutral collisions would happen for ions transferred from LIT1, which leads to higher trapping efficiency. Resolution of the mass selective ion transfer and ion accumulation efficiency depends on operating parameters of both the first and second ion traps. Results shown in the ion accumulation experiments were collected under optimized conditions. Effects of different parameters on ion accumulation efficiency, such as AC ejection frequency, RF scan speed, trapping voltage on ion trap No. 2 (or q value in the Mathieu equation), can be found in Supporting Information.

ASSOCIATED CONTENT

S Supporting Information *

Additional information as noted in text. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: +86-10-68918123. Author Contributions ∥

Y.W. and X.Z. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by MOST (China) (nos. 2011YQ0900502 and 2012YQ040140-07), NNSF of China (no. 21205005), 1000 Plan (China).

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CONCLUSIONS Methods for mass selective ion transfer and accumulation within quadrupole ion trap arrays were proposed and demonstrated on two sets of ion trap arrays. A total of three linear ion traps with different geometries were fabricated and tested, and two ion traps were chosen and used in each set of the ion trap array. Randomly selected ions in LIT1 could be transferred and accumulated in LIT2 or LIT3. In optimized conditions, a mass selective ion transfer efficiency of 91.5% could be achieved, and the intensity of selected ion could be enhanced by ∼2.2 times. With the new tandem MS methodology, multiple precursor ions were analyzed in a single MS scan, which could save ∼40% analysis time (for three precursor ions). Additional studies will be carried out to further optimize the ion trap array, as well as apply proposed methods in the study of gas-phase ion reactions. For instance, product ions from an electron transfer dissociation (ETD) reaction could be transferred and accumulated in the second ion trap to prevent further reactions or fragmentations, which could not be accomplished with current commercial instruments. 10169

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