Ion Source Multiplexing on a Single Mass Spectrometer - Analytical

Article pubs.acs.org/ac

Cite This: Anal. Chem. XXXX, XXX, XXX−XXX

Ion Source Multiplexing on a Single Mass Spectrometer Yury Kostyukevich†,‡,§ and Eugene Nikolaev*,†,‡,§ †

Skolkovo Institute of Science and Technology Novaya Street, 100, Skolkovo 143025, Russian Federation Institute for Energy Problems of Chemical Physics Russian Academy of Sciences Leninskij prospekt 38 k.2, 119334 Moscow, Russia § Moscow Institute of Physics and Technology, 141700 Dolgoprudnyi, Moscow Region, Russia ‡

S Supporting Information *

ABSTRACT: We present the simple approach for the combination of different ion sources on a single mass spectrometer without any interference between them. Each ion source can be positioned as far as 1 m from the mass spectrometer; ions are transported by the means of flexible copper tubes, which are connected, to the separate inlet capillaries. Special valves enable switching channels on and off. Using this approach, we successfully combined native electrospray ionization (ESI), regular ESI, β-electrons ionization, and atmospheric pressure photoionization (APPI) of thermally desorbed vapors of petroleum on a single mass spectrometer. In addition, separate channels allow infusing internal calibration mixture or performing ion molecular reactions in one channel and using the other as a reference. Using this idea, we have developed an original sequential window acquisition of all theoretical mass spectra (SWATH MS) approach in which peptide ions are transported in different channels, one of which is heated to high temperature so that ions are thermally fragmented, and the other channel ensures the presence of nonfragmented ions in the spectrum. Also, we demonstrated the possibility to perform gas phase H/D exchange reaction in one channel and using another as reference. Use of valves makes it possible to exclude any interference between them. Thus, we have demonstrated the possibility to create a multichannel system in which ions would be transported through several inlet tubes in which different ion molecular reactions such as Paternò−Büchi, ozonation, or H/D exchange will occur. Comparison of mass spectra recorded when different channels are open will provide structural and chemical information about unknown species.

T

sources. McEwen and McKay demonstrated the combination of LC/MS and GC/MS,11 Kothari et al. demonstrated Multiplexed Four-Channel Rectilinear Ion Trap Mass Spectrometry12 in which ions from four independent ion sources are analyzed by four independent ion traps housed in a single vacuum manifold. Many multiple sprayer systems in which channels could be triggered either by electric lenses13,14 or by a mechanical valves were developed.15 With the introduction of the ion funnel, which can effectively gather ions, it became possible to develop a multiple inlet systems in which ions from different sources are transported into the fore vacuum region through different inlet capillaries.16 Using such a system, it is possible to switch different changes by a means of electric lenses, continuously infuse internal calibration mixture,17−19 and improve sensitivity by placing an inlet capillary orthogonal to the ion funnel.20 At the same time it may be useful to use the multiple inlet system in combination with ion−molecule reactions under atmospheric pressure such as ozonation21 and Paternò−Büchi22

he high variety of species that need to be investigated by mass spectrometry has determined the development and use of different ion sources. For example, electrospray ionization (ESI)1 is one of the most suitable ion sources for investigation of peptides and proteins, though solution composition and parameters of the ion transfer system (temperature and voltages) are different for regular and native ESI, which should be more soft and preserve native structure and conformation of molecule.2,3 Hormones can be investigated using atmospheric pressure chemical ionization (APCI) and atmospheric pressure photoionization (APPI).4 For investigation of petroleum, both ESI and APPI are suitable.5−8 For the analysis of impurities in the air, the radioactive ion source-contained beta emitter is effective. Many laboratories cannot afford purchasing different mass spectrometers for investigation of different samples, so all experiments are normally performed on the same equipment, meanwhile changing and optimization of ion sources consumes considerable time. Also, sometimes there is a need to combine ions produced from different ion sources, for example when investigating reactions of ions9 including ions with different polarities10 or when continuously infusing an internal calibration standard. Many laboratories have dedicated their efforts to the development of approaches for combination of different ion © XXXX American Chemical Society

Received: January 2, 2018 Accepted: February 14, 2018 Published: February 14, 2018 A

DOI: 10.1021/acs.analchem.8b00027 Anal. Chem. XXXX, XXX, XXX−XXX

Article

Analytical Chemistry reaction for the determination of the double bond position in lipids, H/D exchange7,8,23−27 for the enumeration of the number of functional groups (−OH, −NH and others), and thermal dissociation28−31 for peptide identification and others.32−35 Using the multiple inlet system and the assumption that all chemical reactions occur at the atmospheric pressure before fore vacuum, it is possible to develop a system in which ions would be subjected in-parallel to the number of chemical reactions (ozonation, thermal dissociation etc.) while through one channel will be always transported parent ions. Using this system it will be possible by switching channels rapidly obtain structural information about unknown sample. Ideally, this could be done within the chromatographic peak elution time. Here we present our approach to the development of such a system.

■

METHODS Samples. Streptavidin (53 kDa) was purchased from Imtek company(Moscow, Russia). It was dissolved to concentration 2 × 10−5 M, solvent composition was 99:1 H2O:Formic Acid. Ubiquitin was purchased by Sigma-Aldrich (St. Louis, USA). It was dissolved to the concentration 10−6 M, and solvent composition was 49:50:1 H2O:MeOH:Formic Acid. The Suwannee river natural organic matter (SRNOM) was dissolved in MeOH to concentration 1 g/L. Crude oil was used without any treatment. Phosphorous acid was dissolved in MeOH:H2O to concentration 0.01 g/L. Cytohrome C digest (1.6 nmole) was purchased from Thermo. D2O was purchased from Neogaz company (Moscow, Russia). Enrichment of D2O was 99.9%. Other chemicals were purchased from Sigma and were analytical grade or higher. MS Analysis. All experiments were performed on a modified QExactive orbitrap mass spectrometer (Thermo) with installed ion funnel and fore vacuum matrix assisted lased desorption ionization (MALDI) system (Spectroglyph). Mass spectra were recorded by orbitrap with the resolving power 140 000. The front panel with the MALDI translational stage was replaced with a specially developed plate with several inlet capillaries. The inner diameter of inlet capillary was 0.7 mm. For the experiment with multiple ion sources, copper tubes were connected to inlet capillaries. For switching gas flow in channels on and off, we used regular ball valves COMEX 124/G1 1/8″ HH or Camozzi 2930 1/8″. The inner diameter of valves was 1/8″. For experiments with thermal dissociation, stainless steel tubes were connected to inlet capillaries. One of the tubes was wrapped in a special heat resistant cable with a nichrome conductor in the magnesium oxide and steel braid. This cable allowed heating of the extended capillary to 600 °C. The temperature was measured with a thermocouple attached to the capillary. The temperature variation at different capillary positions and over a single experiment was found to be less than 5 °C. More details about the setup can be found elsewhere.36 In-ESI Source H/D Exchange. To create an atmosphere saturated with the vapors of the D2O 600 μL of solvent were placed on a copper plate positioned at approximately 7 mm below the ESI needle. Due to the evaporation of the droplet, an atmosphere of the saturated D2O vapors is created inside the transfer tube. More details about the method used can be found elsewhere.24

Figure 1. Different designs of the multiplexed ion sources. (A) Dual electrospray source (Schneider, Douglas and Chen): (1) sample in, (2) high voltage. (B) Multi source, multi path mass spectrometer (Loucks and Houtz): (1) inlet capillaries, (2) skimmer, (3) ion optics, (4) mass analyzer. (C) Dual ESI+APCI source (Cheng, Jhang, Huang and Shiea): (1) stainless steel tube, (2) ring electrode, (3) glass tube. (D) dualchannel ion funnel electrospray ionization source with jet disrupter (Tang, Tolmachev, Nikolaev, Zhang, Belov, Udseth, and Smith). (E) rapidly interchangeable source (ESI, APCI, APPI), Thermo and other companies. (F) multiplexed ion source with ball valves used in the present paper.

several ion sources near the inlet capillary14 (Figure 1A). Unfortunately, in such design, different ion sources would affect each other, so it would not be possible to create different ionization conditions for each source. Most expensive and complicated design is presented in the Figure 2B. Here independent ion transmission systems go to the single mass analyzer.12,37 Such design enables using many ion sources simultaneously and independently, but it is impossible to increase the number of sources without rebuilding of the whole device. A dual ionization source combining ESI and atmospheric pressure chemical ionization (APCI) was developed38 (Figure 1C). In this source a discharge can be created around ESI needle, which activates a APCI mode. Use of ion funnel, which can effectively gather ions, considerably simplifies the developing of the multiplexed ion sources.17−19 Indeed, ions from different sources could be transferred into the fore vacuum part by independent capillaries and gathered by the ion funnel (Figure 1D). Almost all commercial mass spectrometers are equipped with rapidly interchangeable sources in which it takes several minutes to replace the ESI probe for the APCI probe39 (Figure 1E). Our approach is presented in Figure 1F, and it based on the use of the ion funnel, but we also use ball valves to regulate (or terminate) the gas flow inside inlet capillaries. The design of the developed multiplexed ion source is presented in Figure 2. Five independent inlet capillaries are connected to copper tubes (inner diameter 1.5 mm) with valves that enable switching channels on and off. The vacuum plate is made from 10 mm opaque organic glass, and inlet capillaries are fastened in a special manifold manufactured on 3D printer. Each tube goes to different ion sources: APPI, regular ESI, native ESI and radioactive source. Tubes 2 and 3 have different length (1.5m and 5m) correspondingly and go to the same ion source. For ESI source we used dispensable medical syringes with volume 0.3 mL

■

RESULTS AND DISCUSSION There are several approaches to the developing of a multiplexed ion source (Figure 1). The most simple way is just positioning B

DOI: 10.1021/acs.analchem.8b00027 Anal. Chem. XXXX, XXX, XXX−XXX

Article

Analytical Chemistry

Figure 2. Developed multiplexed ion source. (A) Multiplexed ion source with 5 independent inlets; tubes go to different ion sources: (1) thermal desorption of oil + APPI, (2) ESI of ubiquitin, length of tube 1.5 m, (3) ESI of ubiquitin, length of tube 5 m, (4) native ESI of streptavidin, (5) radioactive ionization of air impurities, (6) manifold for connecting inlet capillaries and copper tubes. (B) Design of the ion source for thermal desorption of oil + APPI. (C) ESI source based on dispensable medical syringes. (D) Radioactive (3H) ion source. (E) inlet capillaries inside vacuum system. Vacuum plate is made from opaque organic glass. 17

O/18O is very low, such clusters can be effectively used for mass calibration. By varying the flow rate trough different channels, it is possible to obtain the desired intensities of calibrant and sample under investigation. The development of the ion source multiplexing is simple and scalable. Indeed, it is possible to insert several additional inlet capillaries and, by means of transfer tubes with valves, to distance an ion sources from the mass spectrometer to 1.5 m. In this case, several researchers could work simultaneously developing and optimizing their own ion sources without affecting each other. Opening the valve is all that is required to obtain a mass spectrum. The disadvantage of our approach is the inevitable loss of ions in the long transfer tubes. The transport of ions through long capillaries, both metal and glass, was previously studied experimentally and theoretically.42−44 It is known that major ion loss is associated with the radial diffusion and space charge expansion that cause ions to hit walls of the transfer capillary. The ion loss due to the reactions with the transfer gas is considered negligible. For cylindrical capillary ions, loss due to the diffusion can be estimated theoretically.42 Time that ions spend inside capillary is given by

and outer diameter of needle 0.3 mm. APPI ion source (Figure 2B) consists of thermal desorber and vacuum UV lamp (Chromdet-Ecology Company, Russia). This lamp produces photons with energy 10 and 10.6 eV. Twenty milligrams of the crude oil was used in each experiment; more details about this ion source can be found elsewhere.40 Radioactive ion source consists of 3H isotope dissolved in platinum ring that produce 5.6 keV electrons that produce primary ions from ambient air molecules. Ionization of the analyte occurs as the result of the set of ion− molecule reactions; only a very small (negligible) part of analyte molecules is ionized directly by beta electrons. The results of the investigation of the multiplexed ion source are presented in Figure 3 (see also Supporting Information Figures S1−S5). All ion sources were turned on, and different channels were switched on and off using valves. The dependence of total ion current (TIC) on the time and corresponding mass spectra are presented in the Figure 3. It can be seen that in case of radioactive ion source that is connected to the inlet capillary through a short tube the shape of TIC is almost rectangular. The tube to the APPI source has length ∼40 cm, so the shape of TIC is smoother because of the gas dynamic effects. The tube to the regular ESI source is 1.5 m long, but ions passes through and yield a good spectrum. We experimented with the 5 m long tube, but ions did not pass through. For experiment with the native ESI source we choose tetramers of streptavidin. Because in those experiments the transfer tube is not heated, molecules of solvent are not stripped from the complex. The observation of narrow peaks from noncovalent protein complexes generally requires adjusting the desolvating capillary temperature or the ion source collision energy to just below the dissociation threshold.3,41 We have demonstrated this in Figure 4A; the native ESI ion source was optimized and we also opened the channel leading to the APPI source. We have simultaneously acquired broadband spectra of crude oil vapors ionized by APPI and streptavidin tetramers ionized by native ESI. No interferences were observed between different ion sources. The developed multiplexed ion source can be used for the continuous internal calibration. In Figure 4B, the independent infusion and detection of ions produced by two separate ESI sources in negative mode clusters of phosphorus acid and SRNOMis demonstrated. Clusters of phosphorus acid have molecular formula [(H3PO4)nH]−, they span a wide mass range, and because phosphorus has only one stable isotope and natural abundance of 2H and

t inside =

πd 2L 4Q

(1)

Here d is capillary diameter, L is capillary length, and Q is gas throughput, which can be estimated using Poiseuille’s equation: ⎛ πd 4 ⎞ Q=⎜ ⎟ΔP ⎝ 128ηL ⎠

(2)

Here ΔP is pressure drop (1 amt), and η is viscosity of the gas. Ion density distribution (ρ) in the cylinder due to the diffusion to the walls can be obtained as the solution of time-dependent diffusion equation in cylindrical coordinates with the zero ion density on the walls. The solution is ρ = ρ0 e−t / τ τ= C

d2 9.6D

(3) DOI: 10.1021/acs.analchem.8b00027 Anal. Chem. XXXX, XXX, XXX−XXX

Article

Analytical Chemistry

Figure 3. Dependence of TIC on the time, extracted TIC for different m/z ranges, and recorded mass spectra at certain times. The modulation of the full TIC was achieved by switching valves on and off. The sequence of the valve controls is given in the Supporting Information. The extracted TIC was obtained from the full TIC for the most intensive peak corresponding to the particular sample. Mass spectra are given for the cases when only the corresponding channel was open and other channels were closed. The following sources and samples were used: APPI−crude oil, radioactive air impurities, regular ESI−ubiquitin, and native ESI−streptavidin tetramers.

which is heated to 500 °C to induce thermal dissociation. The second channel is kept at room temperature. Using valves, it is possible to switch channels on and off (see Figure 5B1,B2) or regulate flow rate trough channels. Because increasing flow rate corresponds to the increase of intensities of ions that are transported through this channel, it is possible to regulate the intensities of parent ions and fragments in the resulting mass spectrum. In Figure 5C1−C3 are presented cases when heated capillary is blocked (Figure 4C3), nonheated capillary is blocked (Figure 5C2), and when flow rates through channels are regulated in such a way that both parent ions and fragments are present in spectrum. The possibility to regulate intensities of parent and fragment ions of ubiquitin is demonstrated. The developed system can be used in combination with liquid chromatography. For such experiments we used Cow

Here D is the diffusion constant. Combining eqs 1−3, Lin and Sunner derived a rule that, for a typical ion (D ∼ 0.05 cm2/s) in air (η ∼ 1.8 × 10−4 Pa·s), the ion transmission is effective when d > 1.06 × 10−2 L

(4)

Here L is measured in cm. For a 1 m long capillary, the transition is effective when d > 1 mm. We used tubes with inner diameter 1.5 mm, so ion transition is still effective. Using the independence of different channels, it is possible to develop a system in which ions (produced by the same or different ion sources) would be subjected to the ion-molecular reactions, such as thermal fragmentation or H/D exchange in such a way that nonmodified parent ions always pass through one channel. In Figure 5A is presented the design of an ion source in which ions produced by ESI are split into two capillaries, one of D

DOI: 10.1021/acs.analchem.8b00027 Anal. Chem. XXXX, XXX, XXX−XXX

Article

Analytical Chemistry

Figure 4. Simultanious infusion and detection. (A) Simultaneous infusion and detection of crude oil ions produced by APPI of thermally desorbed vapors and streptavidin tetramers produced by native ESI. Dimensions and temperature of the ion transport system were optimized. (B) Simultaneous infusion and detection of ions produced by two different ESI sources: clusters of phosphorus acid and SRDOM.

Figure 5. Thermal dissociation of ubiquitin in a multiplexed ion source; valves are used to regulate the flow rate trough channels. (A) Design of the ion source. (B1) TIC of parent ion. (B2) TIC of fragments. (C1) Recorded mass spectrum when valves are open in such a way that both fragment and parent ions are observed. (C2) Only heated channel is open. (C3) Only non heated channel is open. Extracted TIC from the total TIC for corresponding ions is shown.

We can see that, by means of valves, it is possible to switch different channels and regulate flow rate in channels that in the resulting mass spectrum would be observed in both parent and fragment ions. Using the developed approach, it may be possible

Cytochrome C digest. Flow gradient is given in Supporting Figure S6. This digest contains several tryptic peptides that are presented in Table 1. We used the same setup that was used for investigation of ubiquitin. The results are presented in Figure 6. E

DOI: 10.1021/acs.analchem.8b00027 Anal. Chem. XXXX, XXX, XXX−XXX

Article

Analytical Chemistry

desolvating capillary. Because of the evaporation, the desolvating capillary becomes saturated with D2O vapors, ions interact with D2O, and exchange its labile hydrogens for deuterium. Increase of the desolvating capillary temperature results in the increase of the reaction degree. Using a multiplexed ion source, it is possible to rapidly switch between the channel in which H/D reaction takes place and the reference channel. The design of the experimental setup is presented in Figure 7A. Two inlet capillaries are used. The heated tube is connected through the valve to the closed ESI chamber. D2O is added to this chamber. The other capillary is connected through the valve to another ESI source. The results of the experiment are presented in Figure 7B1−B3 and Figure 7C1−C3. It can be seen that using valves, we can rapidly switch between channels in which gas phase reaction occurs and the reference channel. Values of m/z when only one channel is open remained the same and did not change during the whole experiment. We can see in Figure 7C1−C3 that when both channels are open, the m/z of reference ions increases, and the m/z of ions that pass through channel with D2O decreases. This can be explained by the assumption that H/D reaction can partially occur in the ion funnel, so reference ions also exchange some of the most labile hydrogens for deuterium. In addition, through the reference channel, atmospheric moisture penetrates to the ion funnel region, and the ion coming from the heated tube experiences back exchange. When only one channel is open, this effect is not observed.

Table 1. Composition of the Cytohrome C Digest no.

retention time (min)

sequence

monoisotopic mass

1 2 3 4 5 6 7 8 9 10

18.23 19.07 20.04 22.40 24.78 29.03 29.40 33.5 39.07 41.98

KYIPGTK YIPGTK IFVQK KTGQAPGFSYTDANK TGQAPGFSYTDANK TGPNLHGLFGR MIFAGIK EDLIAYLK GITWGEETLMEYLEPKK GITWGEETLMEYLEPK

805.5 677.4 633.4 1583.8 1455.7 1167.6 778.4 963.5 2137.0 2008.9

to develop a novel concept of SWATH MS45 in which parent ions are observed simultaneously with the fragment ions in the same mass spectrum. Unfortunately, currently we have faced several obstacles: (1) singly charged peptides require higher temperatures for thermal dissociation, and this dissociation does not yield many fragments; (2) thermal dissociation at the atmospheric pressure fragments all ions even those with m/z outside of the acquisition window, but fragments of those ions can be observed; (3) different ions have different activation energies for thermal dissociation, so low abundant ions with high activation energy may be mistakenly considered as fragments. We could not overcome those obstacles, but we believe that use of special software for data processing,46 or other approaches for fragmentation47,48 may help to do it in the future. It is also possible to couple the multiplexed ion source to the gas phase H/D exchange reaction. Recently we have presented a simple approach to perform in-ESI source H/D exchange.24,31,49−52 Droplet of D2O is placed beneath the

■

CONCLUSION We have presented a novel approach to the combination of different ion sources on a single mass spectrometer. By using separate inlet capillaries and relatively long transfer tubes with valves, we have succeeded in combining four different ion sources: APPI, radioactive ion source, native ESI, and regular

Figure 6. Coupling of a multiplexed ion source with liquid chromatography. (A1) Recorded TIC chromatograms when valves are open in such a way that both fragment and parent ions are observed. (A2) Only heated channel is open. (A3) Only non heated channel is open. (B1) Recorded mass spectrum of KTGQAPGFSYTDANK (retention time 22.4 min) when valves are open in such a way that both fragment and parent ions are observed. (B2) Only heated channel is open. (B3) Only non heated channel is open. (C1) Recorded mass spectrum of TGPNLHGLFGR (retention time 29.03 min) when valves are open in such a way that both fragment and parent ions are observed. (C2) Only heated channel is open. (C3) Only non heated channel is open. F

DOI: 10.1021/acs.analchem.8b00027 Anal. Chem. XXXX, XXX, XXX−XXX

Article

Analytical Chemistry

Figure 7. Coupling of multiplexed ion source to in-ESI source H/D exchange reaction. (A) Schematic representation of the experimental setup. (B1) TIC of parent ion. (B2) TIC of ion after H/D exchange. (C1) Recorded mass spectrum of M9+ when both valves are open. (C2) Only heated channel with D2O vapors is open. (C3) Only non heated channel is open. (D1) Recorded mass spectrum of M5+ when both valves are open. (D2) Only heated channel with D2O vapors is open. (D3) Only non heated channel is open. Time is given in minutes.

■

ESI. Switching between channels takes less than 1 s, and no interference between channels was observed. Such different objects as crude oil and streptavidin tetramers can be infused and recorded simultaneously. The possibility to transport ions through a 1.5 long tube makes it possible to assemble different ion sources on different working places that would not interfere with each other. Use of our approach considerably expands the capability of gas phase chemistry to the investigation of structure of unknown sample. Indeed, ions produced from the same ion source, possibly preselected by filed asymmetric ion mobility spectrometry (FAIMS), could be split into different transfer tubes in which different gas phase reactions occur. One of the channels may be kept as a reference. We have demonstrated such idea for thermal dissociation and gas phase H/D exchange reactions. Using valves, it is possible to rapidly switch between different channels, and it was proved that channels do not affect one another. Comparison of mass spectra recorded when different channels are open will provide structural and chemical information about unknown species.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.analchem.8b00027.

■

(PDF)

AUTHOR INFORMATION

Corresponding Author

*Eugene Nikolaev: [email protected]. ORCID

Yury Kostyukevich: 0000-0002-1955-9336 Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Authors are very thankful to the machinist Vladimir Kostuchenko for the help in the developing of the experimental setup. Funding

The research was supported by the Russian Scientific Foundation Grant No. 14-24-00114. G

DOI: 10.1021/acs.analchem.8b00027 Anal. Chem. XXXX, XXX, XXX−XXX

Article

Analytical Chemistry Notes

(33) Kostyukevich, Y.; Kononikhin, A.; Popov, I.; Nikolaev, E. Eur. J. Mass Spectrom. 2015, 21, 109−113. (34) Kharlamova, A.; DeMuth, J. C.; McLuckey, S. A. J. Am. Soc. Mass Spectrom. 2012, 23, 88−101. (35) Zherebker, A.; Kostyukevich, Y.; Kononikhin, A.; Roznyatovsky, V. A.; Popov, I.; Grishin, Y. K.; Perminova, I. V.; Nikolaev, E. Analyst 2016, 141, 2426−2434. (36) Kostyukevich, Y.; Kononikhin, A.; Popov, I.; Nikolaev, E. J. Mass Spectrom. 2017, 52, 204. (37) Loucks, H.; Houtz, G. U.S. Patent 20080087813A1, 2006. (38) Cheng, S. C.; Jhang, S. S.; Huang, M. Z.; Shiea, J. Anal. Chem. 2015, 87, 1743−1748. (39) Adamov, A.; Mauriala, T.; Teplov, V.; Laakia, J.; Pedersen, C. S.; Kotiaho, T.; Sysoev, A. A. Int. J. Mass Spectrom. 2010, 298, 24−29. (40) Zherebker, A. Y.; Perminova, I.; Konstantinov, A.; Volikov, A.; Kostyukevich, Y. I.; Kononikhin, A.; Nikolaev, E. J. Anal. Chem. 2016, 71, 372−378. (41) Blankenship, R.; Zhang, H.; Huang, R.; Cui, W. D.; Harrington, L.; Jiang, J.; Wen, J. Z.; Gross, M. Protein Sci. 2012, 21, 56. (42) Lin, B.; Sunner, J. J. Am. Soc. Mass Spectrom. 1994, 5, 873−885. (43) Puton, J.; Jasek, K.; Anttalainen, O. Int. J. Ion Mobility Spectrom. 2012, 15, 239−246. (44) Garimella, S.; Xu, W.; Huang, G.; Harper, J. D.; Cooks, R. G.; Ouyang, Z. J. Mass Spectrom. 2012, 47, 201−207. (45) Gillet, L. C.; Navarro, P.; Tate, S.; Rost, H.; Selevsek, N.; Reiter, L.; Bonner, R.; Aebersold, R. Mol. Cell Proteomics 2012, 11, O111.016717. (46) Rost, H. L.; Rosenberger, G.; Navarro, P.; Gillet, L.; Miladinovic, S. M.; Schubert, O. T.; Wolski, W.; Collins, B. C.; Malmstrom, J.; Malmstrom, L.; Aebersold, R. Nat. Biotechnol. 2014, 32, 219−223. (47) Berkout, V. D.; Doroshenko, V. M. Int. J. Mass Spectrom. 2012, 325-327, 113−120. (48) Vilkov, A. N.; Laiko, V. V.; Doroshenko, V. M. J. Mass Spectrom. 2009, 44, 477−484. (49) Kostyukevich, Y.; Kononikhin, A.; Zherebker, A.; Popov, I.; Perminova, I.; Nikolaev, E. Anal. Bioanal. Chem. 2014, 406, 6655−6664. (50) Kostyukevich, Y.; Kononikhin, A.; Popov, I.; Kharybin, O.; Perminova, I.; Konstantinov, A.; Nikolaev, E. Anal. Chem. 2013, 85, 11007−11013. (51) Kostyukevich, Y.; Kononikhin, A.; Popov, I.; Nikolaev, E. Anal. Chem. 2014, 86, 2595−2600. (52) Kostyukevich, Y.; Kononikhin, A.; Popov, I.; Nikolaev, E. J. Mass Spectrom. 2017, 52, 204−209.

The authors declare no competing financial interest.

■

REFERENCES

(1) Yamashita, M.; Fenn, J. B. J. Phys. Chem. 1984, 88, 4451−4459. (2) Li, H. L.; Wolff, J. J.; Van Orden, S. L.; Loo, J. A. Anal. Chem. 2014, 86, 317−320. (3) Zhang, H.; Cui, W. D.; Gross, M. L.; Blankenship, R. E. FEBS Lett. 2013, 587, 1012−1020. (4) Gao, W.; Stalder, T.; Foley, P.; Rauh, M.; Deng, H.; Kirschbaum, C. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2013, 928, 1−8. (5) Marshall, A. G.; Rodgers, R. P. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 18090−18095. (6) Qian, K. N.; Robbins, W. K.; Hughey, C. A.; Cooper, H. J.; Rodgers, R. P.; Marshall, A. G. Energy Fuels 2001, 15, 1505−1511. (7) Acter, T.; Kim, D.; Ahmed, A.; Jin, J. M.; Yim, U. H.; Shim, W. J.; Kim, Y. H.; Kim, S. Anal. Bioanal. Chem. 2016, 408, 3281−3293. (8) Ahmed, A.; Kim, S. J. Am. Soc. Mass Spectrom. 2013, 24, 1900− 1905. (9) Lee, J. K.; Kim, S.; Nam, H. G.; Zare, R. N. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 3898−3903. (10) Xia, Y.; Liang, X. R.; McLuckey, S. A. J. Am. Soc. Mass Spectrom. 2005, 16, 1750−1756. (11) McEwen, C. N.; McKay, R. G. J. Am. Soc. Mass Spectrom. 2005, 16, 1730−1738. (12) Kothari, S.; Song, Q. Y.; Xia, Y.; Fico, M.; Taylor, D.; Amy, J. W.; Stafford, G.; Cooks, R. G. Anal. Chem. 2009, 81, 1570−1579. (13) Fung, E. N.; Chu, I. H.; Li, C.; Liu, T. T.; Soares, A.; Morrison, R.; Nomeir, A. A. Rapid Commun. Mass Spectrom. 2003, 17, 2147−2152. (14) Schneider, B. B.; Douglas, D. J.; Chen, D. D. Y. Rapid Commun. Mass Spectrom. 2002, 16, 1982−1990. (15) Park, M. A. U.S. Patent No. 6,657,191, 2003. (16) Kim, T.; Udseth, H. R.; Smith, R. D. Anal. Chem. 2000, 72, 5014− 5019. (17) Belov, M. E.; Zhang, R.; Strittmatter, E. F.; Prior, D. C.; Tang, K.; Smith, R. D. Anal. Chem. 2003, 75, 4195−4205. (18) Tang, K. Q.; Tolmachev, A. V.; Nikolaev, E.; Zhang, R.; Belov, M. E.; Udseth, H. R.; Smith, R. D. Anal. Chem. 2002, 74, 5431−5437. (19) Tang, K.; Belov, M. B.; Tolmachev, A. V.; Udseth, H. R.; Smith, R. D. U.S. Patent No. 6,979,816, 2005. (20) Chen, T. C.; Fillmore, T. L.; Prost, S. A.; Moore, R. J.; Ibrahim, Y. M.; Smith, R. D. Anal. Chem. 2015, 87, 7326−7331. (21) Pham, H. T.; Maccarone, A. T.; Campbell, J. L.; Mitchell, T. W.; Blanksby, S. J. J. Am. Soc. Mass Spectrom. 2013, 24, 286−296. (22) Ma, X. X.; Chong, L.; Tian, R.; Shi, R. Y.; Hu, T. Y.; Ouyang, Z.; Xia, Y. Proc. Natl. Acad. Sci. U. S. A. 2016, 113, 2573−2578. (23) Cho, Y.; Ahmed, A.; Kim, S. Anal. Chem. 2013, 85, 9758−9763. (24) Kostyukevich, Y.; Kononikhin, A.; Popov, I.; Nikolaev, E. Anal. Chem. 2013, 85, 5330−5334. (25) Kostyukevich, Y.; Kononikhin, A.; Popov, I.; Nikolaev, E. J. Mass Spectrom. 2015, 50, 1150−1156. (26) Kostyukevich, Y.; Shulga, A. A.; Kononikhin, A.; Popov, I.; Nikolaev, E.; Deyev, S. Scientific Reports 2017, 7, 6176. (27) Zherebker, A. Y.; Airapetyan, D.; Konstantinov, A. I.; Kostyukevich, Y. I.; Kononikhin, A. S.; Popov, I. A.; Zaitsev, K. V.; Nikolaev, E. N.; Perminova, I. V. Analyst 2015, 140, 4708−4719. (28) Busman, M.; Rockwood, A. L.; Smith, R. D. J. Phys. Chem. 1992, 96, 2397−2400. (29) Rockwood, A. L.; Busman, M.; Udseth, H. R.; Smith, R. D. Rapid Commun. Mass Spectrom. 1991, 5, 582−585. (30) Meot-Ner, M.; Dongre, A. R.; Somogyi, A.; Wysocki, V. H. Rapid Commun. Mass Spectrom. 1995, 9, 829−836. (31) Kostyukevich, Y.; Ovchinnikov, G.; Kononikhin, A.; Popov, I.; Oseledets, I.; Nikolaev, E. Int. J. Mass Spectrom. 2017, DOI: 10.1016/ j.ijms.2017.11.002. (32) Kostyukevich, Y.; Kononikhin, A.; Popov, I.; Indeykina, M.; Kozin, S. A.; Makarov, A. A.; Nikolaev, E. J. Mass Spectrom. 2015, 50, 1079−1087. H

DOI: 10.1021/acs.analchem.8b00027 Anal. Chem. XXXX, XXX, XXX−XXX