New High Resolution Ion Mobility Mass Spectrometer Capable of

Aug 30, 2016 - Jean R. N. Haler , Christopher Kune , Philippe Massonnet , Clothilde Comby-Zerbino , Jan Jordens , Maarten Honing , Ynze Mengerink ...
0 downloads 0 Views 1MB Size
Subscriber access provided by Northern Illinois University

Article

A New High Resolution Ion Mobility Mass Spectrometer Capable of Measurements of Collision Cross Sections from 150-520K Jakub Ujma, Kevin Giles, Michael Morris, and Perdita E. Barran Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.6b01812 • Publication Date (Web): 30 Aug 2016 Downloaded from http://pubs.acs.org on August 31, 2016

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Analytical Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 17

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Analytical Chemistry

A New High Resolution Ion Mobility Mass Spectrometer Capable of Measurements of Collision Cross Sections from 150-520K a

b

b

a

Jakub Ujma, Kevin Giles, Michael Morris, Perdita E. Barran.* a

Michael Barber Centre for Collaborative Mass Spectrometry, Manchester Institute for Biotechnology, University of

Manchester, UK b

Waters, Wilmslow, UK

Abstract We present a new variable temperature (VT), high resolution ion mobility (IM) drift tube coupled to a commercial mass spectrometer (MS). Ions are generated in an electrospray ion source with a sampling cone interface and two stacked ring RF guides which transfer ions into the mobility analyzer located prior to a quadrupole time of flight mass spectrometer. The drift cell can be operated over a pressure range of -1

0.5-3 Torr and a temperature range of 150-520K with applied fields typically between 3 and 14 Vcm . This makes the instrument suitable for rotationally averaged collision cross section (CCS) measurements at low E/N ratios where ions are near thermal equilibrium with the buffer gas. Fundamental studies of the effective ion temperatures are performed at high E/N ratios. An RF Ion trap/buncher is located at the beginning of the drift region which modulates the continuous ion beam into short pulses. Pulses of ions then drift in a linear electric field, which is 50.5 cm long, and are separated according to their mobility in an inert buffer gas. Post drift, an ion funnel focusses the radially spread pulses of ions into the inlet of a commercial MS platform (Micromass QToF2). We present the novel features of this instrument and results from VT-IM-MS experiments on a range of model systems – IMS CCS standards (Agilent ESI Tune Mix), the monomeric protein Ubiquitin (8.6 kDa) and the tetrameric protein complex Concanavalin A (103 kDa). We evaluate the performance of the instrument by comparing ambient

DT

CCSHe of model

compounds with those found in literature. Several effects of temperature on collision cross sections and resolution are observed. For small rigid molecules, changes in resolution are consistent with anticipated thermal diffusion effects. Changes in

DT

CCSHe measurements for these rigid systems at different

temperatures are attributed primarily to the effect of temperature on the long range attractive potential. Similar effects are seen for protein ions at low temperatures, although there is also some evidence for structural transitions. By heating the protein ions their conformational profiles are significantly altered. Very high temperatures narrow the conformational space presented by both Ubiquitin and Concanavalin; it appears that diverse conformational families are “melted” into more homogenous populations. Because of this conformational heterogeneity, the apparent IMS resolution obtained for proteins at ambient and reduced temperatures is an order of magnitude lower than the expected diffusion limited resolution (Rmax). This supports a hypothesis that the broad

DT

CCSHe features frequently observed for proteins do not

correspond to interconverting conformers, rather to high numbers of intrinsically stable structures.

1

ACS Paragon Plus Environment

Analytical Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 17

Introduction Ion mobility - mass spectrometry (IM-MS) is a versatile technique that has experienced a rapid growth over last two decades. In a brief, IM-MS allows simultaneous measurement of an ion’s mass to charge ratio (m/z) and transport properties in a buffer gas medium. Applications include measurements of the collision integral of molecules to gain information about their 3D structures. The collision integral can be expressed as a rotationally averaged collisional cross sectional area (CCS) and correlated with the detected ion abundance, thus providing intuitively interpretable information about the conformational preferences of a particular molecule.1 Investigating those conformational preferences at different temperatures provides insights on the folding energetics of a selected molecular species with a chosen stoichiometry and in an isolated environment. For rigid and thermally stable molecules, variable temperature IM-MS (VT-IM-MS) provides fundamental insights into ion-molecule interaction potentials, an 2,3

important factor for development of the CCS calculation methods.

In the 1960s Earl McDaniel, built the world’s first IM-MS instrumentation to study the fundamental 4

5

properties of ion transport in gases. Thanks to this foundational research ion mobility spectrometry (IMS) was popularised as a low cost, standalone technology for high-throughput detection of explosives and drugs.5–7 Although first demonstrated as an analytical separation technique by Carr in 19778 it was popularised as a way to characterise isobaric species, notably by the groups of Jarrold and Bowers, in the 1990s9–14 Data obtained from VT-IM-MS devices were instrumental in the characterisation of ion-molecule interactions and subsequent developments of computational tools.2,14 Notably the so called “Trajectory Method”, a current benchmark for CCS calculations, heavily relies on the ion-molecule interaction potentials fitted from VT-IM-MS data of C60+.2 Since the application of electrospray to large biomolecules in the late 1980s,

15

mass spectrometry has

been widely used to study complex molecular ions, and significant interest in their gas phase structures has emerged. Covey and Douglas were first to investigate the CCS of protein ions using the kinetic 16

energy loss approach.

Hill et al. coupled ESI with an IM-MS instrument and confirmed that indeed,

different charge states of protein ions can be distinguished with the ion mobility technique.17 Later, Jarrold and Clemmer also coupled an ESI source with their higher resolution drift tube mass spectrometers in order to study the conformations of gaseous protein ions.

18,19

This provided the first evidence that not

only can different charge states of protein ions possess different conformations, but also that a single charge state can present resolvable conformational families. Variable temperature IM-MS has also been 1

used to characterise thermally induced conformational changes in proteins. Notably, Jarrold was the first to develop a VT-IMS cell (6 cm, 100-600K) which was used to study conformational changes in the protein cytochrome C. Early evidence showed that conformational changes of proteins induced by collisional activation are often similar to those induced by raising the temperature of the drift gas.19,20 On the other hand, sub-ambient temperature IM-MS data on proteins remains scarce.

21,22

During the development of high resolution drift

cells with lengths exceeding 100 cm, engineering challenges of combining cryogenics, thermal changes of materials, vacuum and high voltages have been reported.

23

Since the early 2000s, only a handful of 24–26

instruments with variable temperature have been built, but none to date with ion funnels.

In recent

2

ACS Paragon Plus Environment

Page 3 of 17

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Analytical Chemistry

years we have used VT-IM-MS to investigate thermal properties of proteins ranging from 12kDa to 150kDa.

21,22,27

Jarrold et al. constructed a very high temperature drift cell (300-900K, 7.6 cm), used to

investigate phase transitions in metallic clusters.28 The most recently reported temperature controlled drift 29

cell was developed by May and Russell.

Their instrument consists of a 30 cm drift region, has an

operating pressure of 1-5 Torr and a temperature range of 80-400K. Its cryogenic temperature capabilities have been beautifully demonstrated in the analysis of hydrated ions and evolution of water networks.

30–33

During the last decade there has been an explosion of ambient temperature IM-MS research and development of commercial instrumentation.34,35 These instruments made the IM-MS technique available to a wider community, with applications ranging from complex sample analysis to structural biology. We note that despite the great interest in the applications of structure determination, fundamental interactions of large ions with buffer gases remain largely unexplored and VT-IM-MS experiments would certainly be 36,37

helpful for further understanding and development of the computational CCS calculation methods.

Parallel and easy to implement, collision induced annealing38 is enjoying significant attention recently, being applied as a tool for the investigation of protein unfolding in the gas phase.

39

In our view it offers a

great potential for routine investigations, however careful calibration from VT-IM-MS would correlate the effective temperature of the ions with the observed conformational transitions. Here, we present our new VT-IM-MS instrument which successfully combines high transmission, resolving power on the par with state of art commercial IMS platforms with variable temperature capabilities. We present our results obtained on a range of model systems including: a set of IMS standard molecules (fluoro phosphazenes, Agilent Tune Mix), a small protein (Ubiquitin, 8.6 kDa) and a large protein complex (Concanavalin A which presents both as a tetramer 103 kDa and a dimer 51.5 kDa).

Instrument Design A schematic of the instrument is presented in Figure 1. The drift cell instrument features an ESI-IMS-QToF configuration (Figure 1A). The ion source and the IMS assembly are insulated from the mass spectrometer and the pumping system by ceramic flanges (Figure 1. 5, 9). This design allows for independent electrical floating of the ion source and/or IMS assembly up to 2 kV.

3

ACS Paragon Plus Environment

Analytical Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 17

Figure 1. A. Instrument Schematic: (1) Z-Spray ™ ESI Source, (2) first ion tunnel, (3) drift gas inlet, (4) source chamber / second ion tunnel, (5) source ceramic break, (6) external chamber pumping port, (7) external IMS chamber, (8) flexible bellow, (9) ion funnel ceramic break, (10) capacitance manometer port, (11) hexapole chamber, (12) quadrupole mass filter, (13) collsion cell, (14) ToF transfer optics, (15) pusher stack, (16) photomultiplier, (17) multichannel plates, (18) flight tube, (19) reflectron. B. Internal Chamber Assembly: (20) second ion tunnel, (21) cooling copper coil and metal encapsulated resistive heater coil, (22) LN2 port, (23) internal glass tube (shown in blue), (24) ion buncher, (25) ion buncher grids, (26) drift electrodes, (27) ceramic support ring, (28) outer ceramic rods, (29) ion funnel, (30) cone aperture, (31) hexapole lens. C. Electrode Stack Assembly: (32) inner ceramic rods, (33) ion buncher/funnel PCB. D. Cross sectional view of drift electrodes (26), inner ceramic rod (26) and conical spacers (34). Conical spacers ensure the same length of the entire electrode assembly despite differential thermal expansion of materials (depicted by dashed red line), (e) electrode thickness, (s) separation between electrodes. D. Dynamic standoff system ensuring axial alignment despite differential thermal expansion of metallic electrode and ceramic elements. External rods (28) are attached to the ceramic flanges at each end (5,9), inner ceramic rods (32) support the electrode stack via “twisting” standoffs (34).

4

ACS Paragon Plus Environment

Page 5 of 17

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Analytical Chemistry

Ion source has been adapted from a QToF Global instrument (Waters). It features a Z-Spray inlet (1) and two ion tunnels (2, 4). The drift cell assembly (Figure 1B) enclosing the electrode stack has been designed for operation between 120 and 520K. Briefly, the drift cell chamber is of a double jacket design. The external stainless steel chamber (7, 8) encloses the internal insulating tube (23) and the heat transfer system. An internal insulating tube (Pyrex or Alumina) encloses the electrode stack (Figure 1C) and the buffer gas. The flexible bellow forms a part of the external chamber (8) and has an integrated studding on the outside for compression. Using this feature, we are able to compress and seal an internal insulating tube between two ceramic flanges (5, 9). The region between the Pyrex tube and the stainless steel chamber is pumped by a mechanical pump to 3E-2 Torr to provide thermal insulation and to prevent frost formation while cooling. Seals are realised using spring energised, filled PTFE seals (temperature rating 77-600K, Metaplast, Coorstek, USA) and knife-edge copper gaskets. During VT operation, the temperature of the outside chamber varies slightly in line with the thermal expansion of the insulating material inside. This, together with some elasticity of the flexible bellow prevents vacuum failure between the outside chamber and insulating tube. On the outside of the pyrex tube, there is a copper heat exchanger coil (21) connected to LN2 feedthrough (22). The coil is of a serpentine design and has been constructed of two 3/16” copper tubes of 8 meters each. These are connected together to achieve counter flow of coolant around the insulating tube, in the longitudinal direction. As opposed to a typical radially wound coil heat exchanger, we achieve similar efficiency of cooling along the entire length of the insulating tube. The temperatures of the inlet and the outlet of the coolant are measured with two type K thermocouples. House nitrogen gas is passed through a copper coil (1 meter, ¼”) placed inside a liquid nitrogen dewar. The N2 gas cools/liquefies and is forced inside the internal heat exchanger. By changing the flow rate of the supplied N2, we can alter the temperature of the internal heat exchanger. Typically, a 60 deg/hour cooling rate is used, which corresponds to ~2 l/hour of liquid nitrogen used. Once the required temperature is achieved, the flow of coolant is reduced as necessary. Elevated temperatures are achieved via resistive heating. A metal insulated resistive wire (8 meters, 32 Ohm, Inconel, Thermocoax, France) is wound together with copper heat exchanger coil. It can be connected to either a variable AC transformer (Variac) or a DC power supply. Using a Variac with current limited at 4A, we achieve a heating rate of 60 deg/hour. In order to facilitate heat transfer, a small flow of N2 gas through the copper heat exchanger is also used. The temperature of the drift gas is measured via two glass platinum resistance thermometers (Pt100, rated up to 720K, Allectra, UK) which are immersed in the drift gas bath and positioned near the beginning and the end of drift region. Drift gas (typically 1-3 Torr of He) is provided into the drift tube via a Swagelok ¼” fitting compressed on the ceramic flange using a custom made vespel-graphite ferrule (3). A similar connection (10) is used for the connecting pressure manometer (Baratron, MKS Instruments, USA). Thermal transpiration has been considered using the empirical approach presented by Yasumoto.40 We estimate that at 2 Torr of helium at 500K, the error in reading the pressure due to the thermal transpiration effect is less than 0.5%. Inside the VT-IMS assembly, there is the aforementioned electrode stack (Figure 1C), consisting of electrodynamic ion buncher with two grids (24, 25), electrostatic drift electrodes (26) and an 41

electrodynamic ion funnel

(29) at the end of the drift region. The ion buncher (10-200Vp-p, 500 kHz, 140

pF) is 5 cm long and consists of twenty four, 1 mm thick, stainless steel electrodes separated by 1.1 mm

5

ACS Paragon Plus Environment

Analytical Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 17

thick spacers. The internal diameter of the ion buncher electrodes is 15 mm. Two grids are placed th

between the last and 16 electrode (~15 mm apart). The drift region consists of seventy three, 3 mm thick electrodes (26) with a 35 mm internal diameter (i.d.) which are suspended on four rods (32, 6.25 mm diameter) and separated by 3 mm thick, ceramic spacers (34). The ion funnel (0-200 Vp-p, 500 kHz, 140 pF) consists of twenty four, 1 mm thick electrodes with diameters ranging from 35 mm to 8 mm, from the first to the last electrode respectively. Following the ion funnel there is an aperture (0.5 mm) of a conical shape (30). The conical aperture has two functionalities; firstly, the conical shape electrode compensates some adverse effects (“RF trapping/heating”, described later) caused by the relatively thick electrodes chosen because of mechanical strength required for VT operation. Electrodes and spacers have been specially designed to counteract thermal expansion, both longitudinal (Figure 1D) and radial (Figure 1E). As shown in the Figure 1D, rod-mounting holes in all the electrodes have a counter sink (0.5 mm deep, 60 deg) while the spacers have one face chamfered at 60 degrees so that the conical edge of the spacer mates with the counter sink of the electrode. This design eliminates longitudinal thermal changes of the electrode assembly. At high temperatures stainless steel electrodes will expand more than ceramic spacers (red dashed line) and “slide” on the conical spacers. Consequently, although the thickness of the electrodes will increase at high temperature (e’>e), the distance between electrodes will be reduced (s100)23,63,64 and elevated temperature, high pressure IMMS instruments (R>200)

65

however it has enhanced capabilites. It should be noted that the resolving power at

cryogenic temperatures is on the par with state of art ambient commercial IM-MS instrumentation (Agilent IMS-ToF Rexp+1~50, Waters Synapt G2 Rexp+2~38). This clearly demonstrates the advantage of performing measurements at cryogenic temperatures. In the future we will investigate the effect of the temperature on the resolving power with different buffer gasses. We show how ion detection and data acquisition of a ‘vintage’ commercial QToF instrument can be optimised for the IMS investigation of molecules in excess of 100kDa. The capability to perform IM-MS experiments at both sub-ambient and elevated temperatures, introduces a unique way to induce and study conformational changes of an ion of interest and monitor them with an aid of high resolution IMS separation and the detection sensitivity of a commercial mass spectrometer. Conclusions from VT-IM-MS experiments on protein structure are difficult to interpret at this point and more data is necessary to disentangle changes in the ion-molecule interaction potential from structural changes. Several such effects were observed already with our previous generation VT-IM-MS instrument

66

and will be explored in greater detail in the future. We present

DT

CCSHe distributions of

Ubiquitin and Concanavalin A in order to compare our VT data with data presented by others and to highlight structural changes of the protein ions. Changes in

DT

CCSHe observed at cryogenic temperature

agree with the predictions of currently used two temperature kinetic theory and computational tools based on it. However, we note that in the view of an emerging theory which describes the ion-molecule momentum transfer more accurately, the DTCCSHe values reported here should not be deemed absolute.67 Moreover, at this point, we cannot exclude the possibility of multiple simultaneous collisions especially for the Concanavalin A tetramer case at 150K (Supporting Information, Section 1). We envisage that the VTIMS data presented here will be helpful for further understanding of transport phenomena and further optimisation of CCS calculation tools.

Acknowledgements The assistance of mechanical and electronic workshops at the Universities of Edinburgh and Manchester (Andrew Downie, Mike Fisher, David Paden, Richard Taylor, Hunter Scullion, Peter Wilde, Steve Mottley, Sam Mottley, Richard Pallister, Siraj Mohamed) was instrumental during this project. The author would like to thank Jan Commandeur for sharing his knowledge of old Micromass instruments. Kamila Pacholarz is very gratefully acknowledged for her assistance with the Concanavalin A work. EPSRC, 14

ACS Paragon Plus Environment

Page 15 of 17

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Analytical Chemistry

Waters Corp. and the Universities of Edinburgh and Manchester are thanked for their support of a DTA Case studentship to JU, and for allowing us to use many small pieces of preowned no longer needed equipment in this construction. Giles Edwards from the charity RORO is acknowledged for a very reasonable price for an old QToF1 instrument which provided some vital parts used in this project.

References (1)

Mao, Y.; Woenckhaus, J.; Kolafa, J.; Ratner, M. A.; Jarrold, M. F. J. Phys. Chem. B 1999, 103 (45), 10017–10021.

(2)

Mesleh, M. F.; Hunter, J. M.; Shvartsburg, A. A.; Schatz, G. C.; Jarrold, M. F. Energy 1996, 3654 (96), 16082–16086.

(3)

Bleiholder, C.; Wyttenbach, T.; Bowers, M. T. Int. J. Mass Spectrom. 2011, 308 (1), 1–10.

(4)

McDaniel, E. W.; Martin, D. W.; Barnes, W. S. Rev. Sci. Instrum. 1962, 33 (1), 2–7.

(5)

Revercomb, H. E.; Mason, E. A. Anal. Chem. 1975, 47 (7), 970–983.

(6)

Karasek, F. W.; Hill, H. H.; Kim, S. H. J. Chromatogr. 1976, 117, 327–336.

(7)

Karasek, F. W. Anal. Chem. 1974, 46 (8), 710–720.

(8)

Carr, T. W. J. Chromatogr. Sci. 1977, 15 (2), 85–88.

(9)

Jarrold, M. F.; Bower, J. E. J. Chem. Phys. 1992, 96, 9180–9190.

(10)

Jarrold, M. F.; Bower, J. E.; Creegan, K. J. Chem. Phys. 1989, 90, 3615–3628.

(11)

Jarrold, M.; Honea, E. J. Phys. Chem. 1991, 95, 9181–9185.

(12)

von Helden, G.; Kemper, P. R.; Hsu, M.-T.; Bowers, M. T. J. Chem. Phys. 1992, 96 (9), 6591.

(13)

von Helden, G.; Gotts, N. G.; Bowers, M. T. Nature 1993, 363, 60–63.

(14)

von Helden, G.; Wyttenbach, T.; Bowers, M. T. Int. J. Mass Spectrom. Ion Process. 1995, 146147, 349–364.

(15)

Fenn, J. B.; Mann, M.; Meng, C. K. A. I.; Wong, S. F.; Whitehouse, C. M. Science (80-. ). 1989, 246, 64–71.

(16)

Covey, T.; Douglas, D. J. J. Am. Soc. Mass Spectrom. 1993, 4 (8), 616–623.

(17)

Wittmer, D.; Chen, Y. H.; Luckenbill, B.; Hill, H. H. J. Anal. Chem. 1994, 66, 2348–2355.

(18)

Clemmer, D. E.; Hudgins, R. R.; Jarrold, M. F. J. Am. Chem. Soc 1995, 117 (40), 10141–10142.

(19)

Shelimov, K. B.; Clemmer, D. E.; Hudgins, R. R.; Jarrold, M. F. J. Am. Chem. Soc 1997, 119 (9), 2240–2248.

(20)

Clemmer, D. E.; Jarrold, M. F. J. Mass Spectrom. 1997, 32, 577–592.

(21)

Dickinson, E. R.; Jurneczko, E.; Pacholarz, K. J.; Clarke, D. J.; Reeves, M.; Ball, K. L.; Hupp, T. R.; Campopiano, D. J.; Nikolova, P. V; Barran, P. E. Anal. Chem. 2015, 150128125604004.

(22)

Berezovskaya, Y.; Porrini, M.; Barran, P. E. Int. J. Mass Spectrom. 2013, 345-347, 8–18.

(23)

Kemper, P. R.; Dupuis, N. F.; Bowers, M. T. Int. J. Mass Spectrom. 2009, 287 (1-3), 46–57.

(24)

Kemper, P. R.; Bowers, M. T. J. Am. Soc. Mass Spectrom. 1990, 1, 197–207.

(25)

Wyttenbach, T.; Kemper, P. R.; Bowers, M. T. Int. J. Mass Spectrom. 2001, 212 (1-3), 13–23.

(26)

McCullough, B. J.; Kalapothakis, J.; Eastwood, H.; Kemper, P.; MacMillan, D.; Taylor, K.; Dorin, J.; Barran, P. E. Anal. Chem. 2008, 80 (16), 6336–6344. 15

ACS Paragon Plus Environment

Analytical Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 17

(27)

Pacholarz, K. J.; Barran, P. E. Anal. Chem. 2015, 87, 6271–6279.

(28)

Krishnamurty, S.; Chacko, S.; Kanhere, D. G.; Breaux, G. A.; Neal, C. M.; Jarrold, M. F. Phys. Rev. B 2006, 73 (4), 045406.

(29)

May, J. C.; Russell, D. H. J. Am. Soc. Mass Spectrom. 2011, 22 (7), 1134–1145.

(30)

Servage, K. A.; Silveira, J. A.; Fort, K. L.; Russell, D. H. J. Phys. Chem. Lett. 2014, 5, 1825–1830.

(31)

Servage, K. A.; Fort, K. L.; Silveira, J. A.; Shi, L.; Clemmer, D. E.; Russell, D. H. J. Am. Chem. Soc. 2015, 137 (28), 8916–8919.

(32)

Servage, K. A.; Silveira, J. A.; Fort, K. L.; Russell, D. H. J. Phys. Chem. Lett. 2014, 5 (11), 1825– 1830.

(33)

Silveira, J. A.; Servage, K. A.; Gamage, C. M.; Russell, D. H. J. Phys. Chem. A 2013, 117 (5), 953–961.

(34)

Giles, K.; Pringle, S. D.; Worthington, K. R.; Little, D.; Wildgoose, J. L.; Bateman, R. H. Rapid Commun. Mass Spectrom. 2004, 18 (20), 2401–2414.

(35)

May, J. C.; Goodwin, C. R.; Lareau, N. M.; Leaptrot, K. L.; Morris, C. B.; Kurulugama, R. T.; Mordehai, A.; Klein, C.; Barry, W.; Darland, E.; Overney, G.; Imatani, K.; Stafford, G. C.; Fjeldsted, J. C.; McLean, J. a. Anal. Chem. 2014, 86 (4), 2107–2116.

(36)

Bleiholder, C.; Wyttenbach, T.; Bowers, M. T. Biochemistry No. I, 1–22.

(37)

Wyttenbach, T.; Bleiholder, C.; Bowers, M. T. Anal. Chem. 2013, 85 (4), 2191–2199.

(38)

Clemmer, D. E.; Jarrold, M. F. J. Mass Spectrom. 1997, 32 (6), 577–592.

(39)

Hyung, S. J.; Robinson, C. V.; Ruotolo, B. T. Chem. Biol. 2009, 16 (4), 382–390.

(40)

Yasumoto, I. J. Phys. Chem. 1980, 84, 589–593.

(41)

Shaffer, S. A.; Prior, D. C.; Anderson, G. A.; Udseth, H. R.; Smith, R. D. Anal. Chem. 1998, 70 (19), 4111–4119.

(42)

Gerlich, D. In Advances in Chemical Physics: State-Selected and State-to-State Ion-Molecule Reaction Dynamics. Part 1: Experiment; 1992.

(43)

Hoaglund, C. S.; Valentine, S. J.; Sporleder, C. R.; Reilly, J. P.; Clemmer, D. E. Anal. Chem. 1998, 70 (11), 2236–2242.

(44)

Thalassinos, K.; Slade, S. E.; Jennings, K. R.; Scrivens, J. H.; Giles, K.; Wildgoose, J.; Hoyes, J.; Bateman, R. H.; Bowers, M. T. Int. J. Mass Spectrom. 2004, 236 (1-3), 55–63.

(45)

Ibrahim, Y. M.; Baker, E. S.; Danielson, W. F.; Norheim, R. V.; Prior, D. C.; Anderson, G. a.; Belov, M. E.; Smith, R. D. Int. J. Mass Spectrom. 2014, 377, 655–662.

(46)

McLean, J. A.; Ruotolo, B. T.; Gillig, K. J.; Russell, D. H. Int. J. Mass Spectrom. 2005, 240 (3), 301–315.

(47)

Louis, R. H. St.; Hill, H.; Eiceman, G. A. Crit. Rev. Anal. Chem. 1990, 21 (5), 321–355.

(48)

Kurulugama, R. T.; Darland, E.; Kuhlmann, F.; Stafford, G.; Fjeldsted, J. Analyst 2015, 140 (20), 6834–6844.

(49)

Myung, S.; Badman, E. R.; Lee, Y. J.; Clemmer, D. E. J. Phys. Chem. A 2002, 106 (42), 9976– 9982.

(50)

Wyttenbach, T.; Pierson, N. A.; Clemmer, D. E.; Bowers, M. T. Annu. Rev. Phys. Chem. 2014, 65 (1), 175–196.

16

ACS Paragon Plus Environment

Page 17 of 17

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Analytical Chemistry

(51)

Jackson, S. E. Org. Biomol. Chem. 2006, 4 (10), 1845–1853.

(52)

Piana, S.; Lindorff-Larsen, K.; Shaw, D. E. Proc. Natl. Acad. Sci. 2013, 110 (15), 5915–5920.

(53)

Cornilescu, G.; Marquardt, J. L.; Ottiger, M.; Bax, a. J. Am. Chem. Soc. 1998, 120 (27), 6836– 6837.

(54)

Vijay-Kumar, S.; Bugg, C. E.; Wilkinson, K. D.; Cook, W. J. Proc. Natl. Acad. Sci. U. S. A. 1985, 82, 3582–3585.

(55)

Stockman, B. J.; Euvrard, A.; Scahill, T. A. J. Biomol. NMR 1993, 3, 285–296.

(56)

Wyttenbach, T.; Bowers, M. T. J. Phys. Chem. B 2011, 115 (42), 12266–12275.

(57)

Koeniger, S. L.; Merenbloom, S. I.; Sevugarajan, S.; Clemmer, D. E. J. Am. Chem. Soc. 2006, 128 (35), 11713–11719.

(58)

Koeniger, S. L.; Clemmer, D. E. J Am Soc Mass Spectrom 2007, 18 (2), 322–331.

(59)

Wintrode, P. L.; Makhatadze, G. I.; Privalov, P. L. Proteins Struct. Funct. Genet. 1994, 18 (3), 246–253.

(60)

Heck, A. J. R.; van den Heuvel, R. H. H. Mass Spectrom. Rev. 2004, 23 (5), 368–389.

(61)

Light-Wahl, K. J.; Winger, B. E.; Smith, R. D. J. Am. Chem. Soc. 1993, 115 (13), 5869–5870.

(62)

Schwarz, F. P.; Puri, K. D.; Bhat, R. G.; Surolia, A. J. Biol. Chem. 1993, 268 (11), 7668–7677.

(63)

Page, J. S.; Bogdanov, B.; Vilkov, A. N.; Prior, D. C.; Buschbach, M. a; Tang, K.; Smith, R. D. J. Am. Soc. Mass Spectrom. 2005, 16 (2), 244–253.

(64)

Koeniger, S. L.; Merenbloom, S. I.; Valentine, S. J.; Jarrold, M. F.; Udseth, H. R.; Smith, R. D.; Clemmer, D. E. Anal. Chem. 2006, 78 (12), 4161–4174.

(65)

Groessl, M.; Graf, S.; Knochenmuss, R. Analyst 2015, 140 (20), 6904–6911.

(66)

McCullough, B. J.; Kalapothakis, J.; Eastwood, H.; Kemper, P.; MacMillan, D.; Taylor, K.; Dorin, J.; Barran, P. E. Anal. Chem. 2008, 80 (16), 6336–6344.

(67)

Siems, W. F.; Viehland, L. A.; Hill, H. H. Anal. Chem. 2012, 84, 9782–9791.

17

ACS Paragon Plus Environment