Continuous Flow Ion Mobility Separation with Mass Spectrometric

Article pubs.acs.org/ac

Continuous Flow Ion Mobility Separation with Mass Spectrometric Detection Using a Nano-Radial Differential Mobility Analyzer at Low Flow Rates N. A. Brunelli,*,† E. L. Neidholdt,‡ K. P. Giapis, R. C. Flagan, and J. L. Beauchamp California Institute of Technology, Pasadena, California 91125, United States ABSTRACT: We describe a hybrid mass-mobility instrument in which a continuous-flow ion mobility classifier is used as a frontend separation device for mass spectrometric analysis of ions generated with an electrospray ionization source. Using nitrogen as a carrier gas, the resolving power of the nano-radial differential mobility analyzer (nRDMA) for nanometer-sized ions is 5−7 for tetraalkylammonium ions. Data are presented demonstrating the ability of the system to resolve the different aggregation and charge states of tetraalkylammonium ions and protonated peptides using a quadrupole ion trap (QIT) mass spectrometer to analyze the mobility-classified ions. Specifically, data are presented for the two charge states of the decapeptide Gramicidin S. A key feature of the new instrument is the ability to continuously transmit ions with specific mobilities to the mass spectrometer for manipulation and analysis.

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Separation with IMS depends on the electrophoretic migration (or drift) of the ionized molecule in an electric field.14 The migration velocity is a direct function of the size, shape, and charge of the ion.15 While mobility and mass of a homologous series of molecular ions may be correlated,15,16 deviations from such correlations can reflect differences in geometric conformation.17 Mobility separation can be achieved either temporally (i.e., drift tubes and Waters SYNAPT18) or spatially (i.e., Thermo Scientific FAIMS and DMAs). In temporal separation, electrostatic gating at the inlet is required to introduce ion packets into a section in which an electric field propels ions through a static or flowing gas (usually antiparallel in direction to the ion motion). The electrostatic gating significantly reduces the duty cycle of these instruments. In spatial separation, the electric field propels ions across (i.e., perpendicular to) a clean sheath-gas flow. As such, ions can be continuously processed through the device. One method of spatial separation is employed in the Thermo Scientific field asymmetric ion mobility spectrometer (FAIMS).19,20 Spatial separation is achieved in FAIMS through alternate application of high and low voltages for different periods of time to electrodes that generate an electric field transverse to the gas flow along the axis of the device, causing ions to migrate in a sawtooth pattern. Separation depends on the ion having differences in mobility at high and low fields; not all ions will have such a difference. The device does not provide a measure of the true mobility of the ion but rather the difference in high and low field mobilities from which a calculation of the true mobility is not amenable.

ethods to separate complex mixtures prior to characterization with mass spectrometry facilitate the analysis of multicomponent mixtures. Such two-dimensional analysis can distinguish between species based on their properties, including geometric conformations, with small or no differences in mass. Geometric differences are often as important as mass and composition in determining properties at the nanoscale. For instance, nanometer-sized gold particles exhibit different plasmon resonances depending upon whether the particle is a sphere, ellipsoid, or rod.1,2 Other techniques, such as electron microscopy, can probe these conformations for inorganic nanomaterials, but similar analysis is substantially more difficult for very small particles3 and complex biological molecules such as proteins whose functions are closely related to their folded conformations. Subtle changes in conformation can be associated with protein misfolding and aggregation, a phenomenon that is intimately related to a number of human diseases, including Alzheimer’s.4 Analytical separation techniques commonly used in conjunction with mass spectrometry (MS) are performed either in the liquid or gas phase. While liquid chromatography (LC) is particularly effective in preseparating protein digests prior to mass spectrometric analysis, separation depends on so many factors that make a priori determination of separation order difficult, whereas dynamics in the gas phase can be predicted to a certain extent. One well-established gas-phase separation technique, ion mobility spectroscopy (IMS), has been employed in a variety of applications due to its resolving power. These applications include analysis of polymer composition,5−7 large protein complexes,8−11 and characterization of carbohydrate structure.12,13 © 2013 American Chemical Society

Received: November 7, 2012 Accepted: April 2, 2013 Published: April 2, 2013 4335

dx.doi.org/10.1021/ac3032417 | Anal. Chem. 2013, 85, 4335−4341

Analytical Chemistry

Article

In previous experiments in which transmitted ions were detected using a Faraday-cup electrometer, the nRDMA was shown to resolve various tetraalkylammonium ions.33 Here, we report on a hybrid instrument in which an electrospray ionization (ESI) source and the nRDMA, both operated at atmospheric pressure, are interfaced to an ion trap mass spectrometer to enable MS analysis of mobility separated, continuously transmitted ions. The interface is particularly simple and robust, with no major modification needed to either the mass spectrometer or the nRDMA. The mobilities and corresponding mass spectra for several alkylammonium salts as well as for the cyclic decapeptide Gramicidin S are reported.

An alternative device that has advanced significantly for spatial mobility separation is the differential mobility analyzer (DMA). The DMA can continuously process ions while achieving separation at a constant voltage that is directly proportional to the inverse mobility, meaning the true ion mobility can be measured. While DMAs were originally constructed to measure particles larger than 10 nm with moderate resolution,21 new designs enabled the detection of much smaller particles.22 Through increasing the flow rate of gas through the DMA23 and using high-precision machining,24 substantial further improvements in mobility resolution have been achieved, but the transmission efficiency was at the time relatively low, requiring long analysis times or high throughputs.25 Recently, new instruments have emerged with significantly increased transmission, allowing analysis times of less than 10 s,11,26 while retaining high resolution operation, including the transversal modulation IMS (TM-IMS)27 and the parallel plate DMA.28 The TM-IMS utilizes two electric fields to both drive the particles from the inlet to the outlet using a constant field and to separate the particles in a perpendicular direction using a sinusoidally varying field that can be frequency modulated to select particles of different mobility. Particles with zero net displacement or on “resonance” with the migration between the inlet and outlet are transmitted. While the electric field enables a low flow rate operation of the device, the device transmits the desired on resonance particles in addition to an undesired steady background of ions, which can theoretically be removed through using two instruments in series. The high resolution and transmission make such a device desirable, but the high degree of overall complexity required to transmit a single mobility ion could limit the actual utilization. The parallel plate DMA offers a simpler device that can still achieve high resolution and transmission. For DMA-MS applications, the device is routinely operated at high flow rates (in the range of 1000 L per minute (LPM)), achieving resolutions greater than 50 routinely and transmissions of approximately 50%.29 The underlying operation principles of this high-performance instrument are similar to the more widely utilized cylindrical30 and radial DMAs,31 requiring particles to migrate across a particle free sheath gas. The high flow rates required for high performance are undesirable, but this limitation has been overcome through recirculating the sheath gas, which introduces the new complications of accumulation of uncharged particles and moisture in the recirculation gas that could impact ion transmission and observed mobility, respectively. These problems have been overcome through flowing the recirculating gas out of the inlet and using an electric field to draw the particles into the inlet. Another problem associated with the high flow rate is that the exact flow rate is unknown. Since the mobility of the transmitted particles depends on the exact value of the flow rate, frequent calibrations are required using known mobility standards.32 Overall, the parallel plate DMA represents the state of the art for DMA-MS measurements as it has considerable performance but at the cost of several added complexities. For some applications, operation at lower gas flow rates and using a simpler interface would be desirable. Herein, a recently demonstrated DMA, the nano-radial differential mobility analyzer (nRDMA), is used for mobility separation with mass spectrometric detection. This analyzer has previously achieved good resolution of nanometer size ions33 with good transmission34 at modest flow rates (10 LPM).

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EXPERIMENTAL SECTION The nRDMA interfaces to the entrance of a mass spectrometer, as shown in Figure 1. The components are assembled in series in

Figure 1. Schematic of nRDMA system interfaced to mass spectrometer. Schematic shows experimental setup used to measure the combined mobility and mass distribution.

the following order: electrospray source, nRDMA, and mass spectrometer with atmospheric pressure inlet (Thermo Scientific LCQ Deca XP ion trap mass spectrometer (ITMS)). This arrangement did not require any special modifications beyond replacing the usual electrospray source with the nRDMA instrument. The ionization source preceding the nRDMA is a home-built electrospray ionization (ESI; needle i.d. 127 μm) emitter used previously.33 This ESI source operates at relatively high liquid flow rates (∼100 μL/min). A second ESI source (needle i.d. 120 μm), shown in Figure 2, is used for Gramicidin S to enable operation at liquid flow rates typical of ESI-MS analysis, using the syringe pump incorporated into the ITMS. For the experiments with Gramicidin S, the ESI source operates at a voltage of +2400 V dc with a liquid flow rate of 5−10 μL/min. Each electrospray source is connected to the nRDMA using standard Swagelok fittings. The nRDMA is positioned in front of the LCQ-MS using a breadboard plate (150 mm × 150 mm) made for mounting optical elements, a pair of custom-built mounting plates, and optic mounting posts (o.d. ≈ 12 mm) as shown in Figure 3. The assembly aligns the sample outlet of the nRDMA with the 4336



Article

After alignment of the nRDMA with the mass spectrometer inlet, the gap for discharge of excess classifier outlet flow is less than 1 mm. The nRDMA is operated in voltage stepping mode35 with a 10 SLM sheath flow rate of nitrogen and an aerosol inlet and outlet flow rate of nitrogen of 0.5 SLM. The DMA is biased with a high voltage power supply (Ultravolt 2 kV supply) that is controlled externally with a LabVIEW (National Instruments, Austin, TX) program and hardware. The program sets the voltage level for each step of the scan and holds it constant for a 30 s interval. The process is repeated for a number of voltages to cover a range of ion mobilities. The voltage range is scanned from 50 to 300 V, which translates into a value of E/P of less than 0.4 V Torr−1 cm−1 for all voltages measured. The LabVIEW program was started at the same time as the time-based scan of the MS and continued for sufficient time to ensure data would be collected over the complete voltage scan. The data were analyzed using a MatLab program that averaged the total signal produced by the transmitted ions over the 30 s interval that the voltage was held constant. Plots depicting the average mass spectra were produced through averaging the signal over the 30 s interval in the mass spectrometry software. Solutions for electrospray were prepared from [CH3(CH2)n]4N+X− (n = 2−7; X = I or Br) salts purchased from Sigma-Aldrich (St. Louis, MO) and used without further purification. Each solution was prepared with an analyte concentration of 30−50 μM in methanol. Solutions of Gramicidin S were prepared from a sample of Gramicidin S hydrochloride, obtained from Sigma Aldrich (St. Louis, MO). The peptide concentration was 175 μM in methanol, with 0.1% acetic acid added to aid in ionization in the positive mode.

Figure 2. Detail of miniaturized electrospray source used in work with Gramicidin S. A 1/8 in. nylon Swagelok tee was modified to accept a metallic counterelectrode. The ESI needle is 26 gauge hypodermic tubing from Small Parts Corporation. Application of high voltage to a needle with a grounded counterelectrode establishes an electric field for electrospray. An aerosol flow of 0.6 SLM of nitrogen is introduced at “gas in” and aerosol to be analyzed exits at “to nRDMA”. The miniaturized electrospray source allowed for liquid flow rates that were similar to a typical electrospray ionization experiment (3−6 μL per min) that makes the experiment compatible with typical commercial instrumentation for ESI using syringe pumps and limited sample volumes.

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RESULTS AND DISCUSSION Mobility Distributions for Alkylammonium Salts. The mobility distribution recorded using the LCQ-MS detector for the monomer of each alkylammonium ion is presented in Figure 4. The molecular ion is detected at approximately the same inverse mobility (1/Z, where Z is the electrophoretic ion mobility) value reported previously when a Faraday cup electrometer was used for detection,33 confirming the identity of the detected ion in the mobility distribution. Table 1 compares the results obtained here to those previously reported in terms of collision cross section, and a good agreement is observed, indicating that detection using the mass spectrometer does not skew mobility values. It is noted that mobility values of transmitted ions are determined by the gas flow rates, electric field, and device geometry, 33 and mobility scales can be calibrated by reference to accepted values.32 For the tetraheptylammonium ion, mass spectrometric analysis of ions observed in an extended voltage scan is performed specifically to analyze the species present in the second and third peaks of the mobility distribution, as shown in Figure 5. These peaks contain composites of the monomers and anions with the molecular formula for the m charged n-mer can be generally written as (A+1)n(X−1)n−m with A+1 representing the positively charged ammonium cation and X−1 the negatively charged halogen anion. As indicated above, the mass spectrum for peak 1 consists only of a single mass at 410.5 m/z, the molecular weight of the tetraheptylammonium cation. The region corresponding to peak 2 consists of two different species as detected in the mass spectrometer. These include singly charged monomer A+1 and singly charged dimer (A+1)2(X−1). The monomer is believed to result from fragmentation of

Figure 3. Photo of nRDMA instrument installed in front of the ion trap mass spectrometer. Mounting is achieved using machined parts. Photograph also shows electrospray source made from the nylon Swagelok fitting, as was used for experiments Gramicidin S. The ESI source used for the tetraalkylammonium ions was described previously.12

atmospheric pressure inlet (API) of the ITMS. Because of the ports on the nRDMA and the construction of the LCQ-MS, the sample outlet of the nRDMA and the API of the LCQ-MS are separated by a distance of 25 mm in the present installation. A Swagelok-to-tube stub (1/4 in. to 1/8 in.) fitting installed on the nRDMA outlet minimizes the gap between the instrument outlet and the atmospheric pressure inlet of the mass spectrometer. 4337



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Figure 4. Inverse mobility distributions using the mass spectrometer as a detector: inverse mobility are recorded with the ITMS as the detector over the voltage range indicated in parentheses for (a) tetrapropylammonium (40−120 V), (b) tetrabutylammonium (60−140 V), (c) tetrapentylammonium (60−150 V), (d) tetrahexylammonium (80−180 V), (e) tetraheptylammonium (120−200 V), (f) tetraoctylammonium (130−210 V) cations.

Despite carefully examining the peak manifold of peak 2, no evidence is observed of the doubly charged tetramer. Peak 3 in the mobility spectrum is comprised of monomer, dimer, trimer, and tetramer ions, suggesting that this peak is not due to a single species. This peak likely results from a number of multiply charged complexes that subsequently fragment after the nRDMA analyzer but before analysis with the mass spectrometer. Such high charging is commonly observed from electrospray sources and could be overcome using a charge reducing device in order to obtain a more extended scan. Mobility Distributions for Gramicidin S. The nRDMA instrument is also demonstrated for the analysis of a biomolecule. Ion mobility-mass spectrometry has previously been applied to the analysis of cyclic peptides.37 The performance of the nRDMA/ITMS for analysis of biomolecules is explored using the cyclic decapeptide Gramicidin S, which has the sequence cyclo-[VOL(dF)P]2, where O is the amino acid ornithine, and dF is D-phenylalanine. Gramicidin S is beneficial for study due to the stability of the peptide and the fact that it typically displays two charge states in an ESI mass spectrum, having either one or both ornithine residues protonated. Figure 6 shows the observed mobility spectrum comprised of three peaks. Peak 1 is found to consist of a single species of 571.3 m/z, corresponding to the doubly charged monomer. Peak 2 is also found to contain a single species of 1141.8 m/z, consistent with the singly charged monomer of Gramicidin S. The mass spectrum recorded for peak 3 again shows the singly charged monomer of Gramicidin S, in higher abundance than in the other peaks. The height of this peak could be modulated in different experiments by changing the

Table 1. Inverse Mobilities for the Alkylammonium Cations As Measured in Previous Work Using Air as the Analysis Gas and This Work Using Nitrogen as the Analysis Gasa collision cross section (Å2)

1/Z (V s cm−2)

1/Z (V s cm−2)

cation

previous work40

this work

previous work32 (air)

this work (N2)

tetrapropylammonium tetrabutylammonium tetrapentylammonium tetrahexylammonium tetraheptylammonium tetraoctylammonium

144 166 190 214 237 258

143 179 197 221 235 257

0.619 0.718

0.603 0.772 0.856 0.964 1.03 1.13

1.03

a Good agreement is achieved in the first experiments with the new nRDMA-MS interface. Further work utilizing more careful calibration of the gas flow and peak fitting should bring currently measured values closer to the calibrated values from the literature.

mobility classified dimers downstream of the nRDMA, but before analysis with the LCQ-MS, as has been observed previously.29,36 Therefore, the recorded signal in the mobility distribution plot corresponds to the total ion current from the MS for simplicity. Peak 2 is found to have a resolution less than theoretically expected, as was observed previously for the dimer peak. It is possible that this could be due to the doubly charged tetramer ((A+1)4(X−1)2), which is expected to have a mobility that is slightly larger than the singly charged dimer (A+1)2(X−1). 4338



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Figure 5. Mobility distributions of tetraheptylammonium for an extended compensation voltage scan and corresponding mass spectra. (a) Inverse mobility spectrum for extended compensation voltage scan. Three peaks are observed. (b) Mass spectrum acquired during elution of peak 1. Tetraheptylammonium monomer is observed. (c) Mass spectrum acquired during elution of peak 2. Monomer and dimer of tetraheptylammonium is observed. Observation of monomer is possibly due to transmission of the dimer and subsequent fragmentation into monomer subunit. (d) Mass spectrum acquired during elution of peak 3. Various multimers of tetraheptylammonium are observed.

spray voltage or liquid flow rate of the ESI source. As this peak depends on the operating conditions of the spray source, it is thought that this peak, like the third peak in the alkylammonium spectrum, may be due to desolvation of mobility classified solvent droplets within the entrance capillary of the mass spectrometer. Similar peaks had previously been attributed to solvent droplets,38 but the composition of those peaks was not assigned. nRDMA as a General Front End Mobility Analyzer for Mass Spectrometers. The nRDMA can easily interface with the ITMS without major modifications to either instrument, making it an IMS system that is well-suited to study a variety of systems from organic ions to biomolecules. Unlike other highresolution DMA instruments, introducing the analyte to the mobility separation region does not require an electric field to draw the ions into the instrument. The minor modifications required do not impact the performance of the nRDMA, as the instrument resolution calculated using the ITMS as the detector is 7 for the tetraheptylammonium monomer, similar to but slightly lower than that observed when using a Faraday cup electrometer to detect the transmitted ions.33 While the resolution is relatively low compared to other high flow rate instruments, the resolution could be readily changed through adjusting the ratio of the sheath to aerosol flow, as has been done with other designs.29 COMSOL Multiphysics simulations reveal that minor modifications to the nRDMA design and an increase in the sheath flow rate should increase the resolution to 30 while using only a sheath flow of 50 SLM that

could be increased further. Finally, the present study only explores the nRDMA/ITMS interface using the Thermo-LCQ, but the nRDMA-MS systems should be universally applicable to all mass spectrometers that possess an atmospheric pressure inlet. In general, the simplicity of the interface makes the nRDMA a powerful tool for front-end mobility separation.

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SUMMARY

We have reported the implementation of a nRDMA-ITMS system whereby ion mobility-MS analysis of organic molecules and small peptides has been achieved. The particular system involved the interfacing of a nRDMA instrument to a laboratory mass spectrometer with an atmospheric pressure inlet in a very simple and effective manner. The identity of mobility-separated ions were confirmed for the homologous series of alkyl ammonium ions, and it was demonstrated the second peak of an extended mobility scan contained both singly charged dimer and doubly charged tetramer. Finally, the two charge states of the cyclic decapeptide Gramicidin S were isolated through mobility separation. A resolution of 5−7 is observed for mobility separated ions with the present embodiment of the nRDMA with the expectation that this can be greatly improved in future designs.39 4339



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Figure 6. (a) Mobility distribution for Gramicidin S for two different electrospray conditions. Peak 1 corresponds to doubly charged monomer that has at a m/z of 571.3 (b); peak 2 corresponds to singly charged monomer that has a m/z of 1141.7 (c). Peak 3 also contains singly charged monomer that has a m/z value of 1141.7 (d). Higher liquid flow rate and lower spray voltage appears to promote formation of droplets relative to ions. The expanded m/z scan for (e) peak 1 and (f) peak 2.

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Notes

AUTHOR INFORMATION

The authors declare no competing financial interest.

Corresponding Author

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*E-mail: [email protected]. Present Addresses

REFERENCES

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†

N.A.B.: Georgia Institute of Technology, Atlanta, Georgia 30332, United States. ‡ E.L.N.: Jet Propulsion Laboratory, 4800 Oak Grove Drive, Pasadena, California 91109, United States. 4340



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Continuous Flow Ion Mobility Separation with Mass Spectrometric

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