Extreme ultraviolet (XUV) radiation: a means of ion activation for

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Extreme ultraviolet (XUV) radiation: a means of ion activation for tandem mass spectrometry Alexandre Giuliani, Jonathan P. Williams, and Martin R. Green Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.8b01789 • Publication Date (Web): 25 May 2018 Downloaded from http://pubs.acs.org on May 25, 2018

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Extreme ultraviolet (XUV) radiation: a means of ion activation for tandem mass spectrometry Alexandre Giuliani [a,b]*, Jonathan P. Williams [c] and Martin R. Green [c]* [a] Synchrotron SOLEIL, L’Orme des Merisiers, F-91190 Gif-sur-Yvette, France, [b] UAR 1008 CEPIA, INRA, F-44316 Nantes, France, [c] Waters Corporation, Stamford Avenue | Altrincham Road, Wilmslow, SK9 4AX, UK Corresponding Authors: * [email protected], * [email protected]

KEYWORDS: Mass spectrometry, tandem mass spectrometry, photoionization, photodissociation, ultraviolet, XUV, fragmentation ABSTRACT: Tandem mass spectrometry has long been established as a corner stone of analytical and structural chemistry. Fast, radical directed dissociation, produced by Electron Transfer and Electron Capture Dissociation (ETD and ECD) has been shown to provide important complimentary information to Collisionally Induced Dissociation (CID). We report the first application of extreme ultraviolet (XUV) lamps to tandem mass spectrometry. These discharge lamps are versatile, robust and low-cost sources of energetic photons (40-80 nm). The coupling of the discharge lamp with a Synapt G2-Si (Waters) Q-ToF mass spectrometer is achieved through a specific trapping scheme in the TriWave region of the instrument, allowing efficient irradiation of the precursor ions. Rich, radical directed, dissociation was produced for a number of model compounds providing unique, complimentary information to existing dissociation techniques.

Mass spectrometry (MS), and in particular tandem mass spectrometry (MS/MS) has developed into a corner stone method in structural and analytical chemistry. Fundamentally, tandem mass spectrometry relies on providing ions of interest with enough internal energy to produce structurally informative product ions. Collisionally Induced Dissociation (CID), which involves multiple low energy inelastic collisions of ions with inert gas molecules,1 continues to be the most common way of ion activation. Despite its universality, CID suffers from limitations inherent to its nature.1 Indeed, the redistribution of vibrational energy during the collisions ultimately leads to dissociation of the weakest bonds. This can result in product ions which provide little structural information. Moreover, for large molecular ions, the amount of deposited internal energy may not be sufficient to produce abundant fragments. These limitations have motivated the search for alternative activation means, such as surface induced dissociation,2 electron capture 3 or transfer 4 dissociation, electron ionisation dissociation,5,6 fast atom bombardment,7 hydrogen attachment/abstraction,8 charge transfer dissociation 9 or photodissocation.10–12 Recently, the use of ultraviolet (UV) photons has attracted considerable interest through successful application to the analysis of small molecules, peptides, nucleic acids, lipids, and proteins.13–19

Photodissociation proceeds from population of excited states after absorption of photons. In the UV region (wavelengths less than 400 nm), photon absorption involves electronic transitions and thus depends on the electronic structure of the molecules.20 Specific chromophores may take part in the process depending on the wavelength of the excitation radiation. In the vacuum UV (VUV) range (157-193 nm), increased numbers of electrons are involved in the electronic transitions compared to in the longer wavelength regions. As a consequence, the photon absorption increases monotonically up to the maximum around 18-20 eV (69 – 62 nm).21 Eventually, enough energy is injected into the system to remove an electron and cause ionisation. For most species, the ionisation threshold lies in the 8 to 15 eV range, even for multiply protonated cations.22,23 It is now well established that above this threshold, photon absorption leads principally to ionisation and the product ions originate from dissociative photoionization (DPI).24,25 The DPI regime, presented in equation 1, is different from UV photodissociation (UVPD) encountered at lower photon energy (equation 2).20 DPI is characterized by removal of one or more electrons from an ion leading to the formation of radical species (equation 1). For cations, this results in an increase in the absolute value of the charge and for anions a reduction of the absolute value of the charge followed by dissociation.

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   →   ●  →   if hυ≥ IE (1)    →  ∗ →   if hυ < IE (2) Typically, photodissociation is achieved using lasers, such as excimer lasers in the VUV range (157-193 nm) 13–15. Recently, photon activation has been reported using lightemitting diodes.26 Nevertheless, the higher photon energy domain and especially the extreme UV (XUV) range (4080 nm) has so far only been probed using very large facilities such as synchrotron radiation sources 27 or free electron lasers.28 However, the XUV domain may also be reached using gas discharge lamp lines. In this work, we report on the coupling of a glow discharge lamp with a Synapt G2-Si mass spectrometer (Waters, Manchester, UK). DPI appears to provide complementary product ion information compared to UVPD and other dissociation techniques.

age of the gate electrodes is increased to confine the ions in the interaction region for a given amount of time. The population of ions within the trapping region is controlled by gating the transmission of ions from the ESI source for a given amount of time into the trapping region. The irradiation time is controlled by varying the time during which the ions are trapped prior to release towards the orthogonal acceleration time of flight (oa-ToF) mass analyser. The trap region consists of a stacked ring ion guide (SRIG). Ions are confined radially during trapping in the radial effective potential well created by application of a radio-frequency potential (RF) to the electrodes. In the present work, the irradiation time was manually adjusted for each compound in the 1 to 2 second range. Another irradiation scheme has been tested in which ions are slowed down within the ion guide by increasing the exit potential, which results in irradiation of a continuous ion beam, but without a defined irradiation time. Both procedures produce identical results. Under normal operation, the trap cell is filled with argon to optimise conditions for CID. However, argon has a relatively high photo-absorption cross section at the helium He(I) radiation wavelengths,30 which could reduce the available photon flux for ion activation. Argon has therefore been replaced by helium in both the trap and transfer regions.

Figure 1. Schematic of the Synapt G2-Si showing the ion path (in blue) and the arrangement of the XUV lamp in the trap region. XUV radiation is delivered through a differentially pumped glass capillary (in blue) positioned in close proximity to the Trap region. Figure 2. Details of Trap-T-Wave region showing the XUV irradiation region. The grey shaded areas represent different groups of electrodes. The form of the potential used for trapping ions (red), irradiation (purple) and releasing ions (green) is shown. The irradiation region is indicated by the purple arrow.

EXPERIMENTAL SECTION Mass spectrometry The experimental setup is depicted in Figure 1. The vacuum lid of the Synapt G2-Si mass spectrometer (Waters, Manchester, UK) has been modified to receive an additional KF-25 port, providing access to the TriWave region of the spectrometer (Figures 1 and 2). A modified gas discharge lamp (UV1 from Prevac, Rogów, Poland), is installed close to the trap region. The lamp is operated typically at 1 mbar of helium (as measured by a capacitance gauge placed on the gas inlet) and with a discharge current of 300 mA sustained by 780 V applied DC potential. An XDS 35i scroll pump (Edwards) is fitted to differentially pump the discharge capillary. The photon beam irradiates an area of ~10 mm along the ion path in the trap region upstream the ion mobility separation (IMS) cell. In order to accumulate ions in the interaction zone, a specific trapping scheme has been established. An axial potential well is created by increasing the voltage of the exit electrodes of the trap region, as shown in Figure 2. This is a similar scheme to that presented in previous work, where ions were trapped in the transfer region of the instrument and subjected to UVPD.29 The volt-

Data Analysis Data has been processed using MassLynx 4.1. (Waters, Manchester, UK). De-isotoping and de-convolution of multiply charged product ions was performed using BayesSpray31.

RESULTS AND DISCUSSION The utility and efficiency of the DPI technique has been evaluated using a range of different classes of small molecules. The applicability of the techniques to polypeptides is explored to contrast with existing UVPD results in the literature.

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Figure 3. DPI (21.22 eV photon energy) tandem mass spectrum of Glu-Fibrinopeptide B [M+2H]2+ (m/z 785.8426). Top panel: raw data, bottom panel: deconvoluted data (using BayesSpray 31).

Figure 4. Tandem mass spectra of singly protonated erythromycin [M+H]+ (m/z 734.47). Top panel: under CID activation with 50 eV collision energy. Bottom panel: under DPI activation using helium radiation (21.22 eV). Product ion peaks are assigned following the convention described in reference 37.

Glu- Fibrinopeptide B is a model peptide of 14 residues, which has been studied by various activation methods such as ECD 32, VUV photodissociation (UVPD) 33, CID (ref. 34 and Figure S1) and femtosecond laser induced dissociation (fsLID) 34. Unsurprisingly, ECD 32 and ETD (figure S2) activations of the triply protonated peptide ion results in a complete c-/z- sequence ion series. Upon CID, the doubly protonated Glu-Fibrinopeptide ion yields an abundant and almost complete y- series of ions (figure S1) 34.) Reilly and co-workers have studied 193 and 157 nm activations of the peptide in both tandem MALDI (matrix assisted laser desorption ionisation) and ion trap arrangements. The 157 nm photon activation yielded more fragments than the 193 nm photon activation, especially in the high mass range, with a complete x- series accompanied by few v- and w- ions 33. In contrast, the product ion spectrum produced by fs-LID is composed of the same b/y- sequence ion series as observed under CID activation along with a few c- and z- ions 34. Specific to the fs-LID activation scheme is the formation of the radical cation and doubly charged product ions arising from tunnelling ionisation 34,35. Similar features are observed in the DPI tandem mass spectrum of Glu-Fibrinopeptide B presented in Figure 3 and listed in Table S1. The dominant product ion is the radical [M+2H]3+● cation accompanied by neutral losses, as previously reported under synchrotron radiation 36, along with the b-/yion series. However, the c- sequence ions are not formed but, akin to the VUV (193 and 157 nm) experiments, x- and v- ions are observed. As described, XUV photons carry enough energy to ionize the precursor ion and initiate DPI. The maximum amount of internal energy released into the products is given by hν – IE, where hν is the photon energy and IE, the ionization energy of the ion. With 21.22 eV photons (58.4 nm) impacting a doubly protonated peptide ion (IE~11 eV 27), up to 10 eV can be deposited in the system. This value is comparable to fs-LID 35 and thus explains the resemblance of the outcome of both techniques. The total sequence coverage obtained from this data was ~ 90%.

The erythromycin molecule, displayed in the inset in figure 4, consists of a 14-membered macrocycle bearing two sugar units, namely D-desoamine and L-mycarose. Tandem mass spectrometry of erythromycin has been reported upon CID activation,37–40 infrared multiphoton dissociation (IRMPD) 40 and also by electron induced dissociation (EID).37 The present CID data (Figure 4, top panel) are in agreement with the earlier reports. The main fragmentation pathway is the loss of mycarose (m/z 576), formation of desosamine ion at m/z 158 and water losses (m/z 716 and 698). IRMPD conditions 40 did not produce substantially different product ions compared to CID. The DPI tandem mass spectrum (Figure 4, bottom panel) is more akin to that reported after EID activation.37 A rich fragmentation pattern is observed, with abundant double fragmentation from the macrocyle. A list of the main fragments is provided in Table S2. Interestingly, product ions resulting from intracyclic cleavages of the sugar moieties are observed, such as m/z 602 (Table S2). These intracylic cleavage product ions allow insights into the structure of the molecule not available by CID alone. Ropartz et al 25,41,42 have studied the effect of high energy photon activation on polysaccharides using synchrotron radiation. XUV photon activation exceeds the ionisation threshold of singly charged carbohydrates and thus did not require the presence of particular chromophores on the chain. The fragments were generated more evenly over the backbone with specific patterns such as X/Y/Z. The absence of neutral losses and double cleavage was noticed. (Figure 5) shows the DPI spectrum of Acarbose using the gas discharge lamp. Acarbose is a pseudo-tetrasaccharide used as an anti-diabetic drug. CID activation of carbohydrates predominantly results in cleavage of the glycosidic bonds and neutral losses yielding limited structural information. Glycosidic bond cleavage leads, in the Dommon and Costello nomenclature43 (Figure S4), to Y, Z and B, C fragments containing the reducing and non-reducing ends, respectively.41 As expected, acarbose forms mainly B ions under CID excitation conditions, as seen in Figure 5 and in Table S3 where the dominant products are listed. In agreement with earlier reports, 25,41,42 XUV irradiation using He(I)

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radiation produces A ions from intra-cyclic cleavages that are not seen upon CID activation conditions, see Figure 4 and Table S4. As noted previously, these fragments are of particular interest for structural studies of oligo-saccharides.41

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for ions of low charge state, such as those formed by Matrix Assisted Laser Desorption Ionisation (MALDI).

ASSOCIATED CONTENT Supporting Information Tandem mass spectra and lists of product ions for GluFibrinopeptide B, Eryrhromycin, Acarbose and poly-propylene glycol (in PDF) are available. The Supporting Information is available free of charge on the ACS Publications website.

AUTHOR INFORMATION Corresponding Author [email protected] [email protected]

Author Contributions

Figure 5. Top panel: CID (50 eV collision energy) and bottom panel DPI (21.22 eV photon energy) tandem mass spectra of protonated acarbose [M+H]+ (m/z 646.256). Fragmentation specific to DPI are indicated in blue.

The manuscript was written through contributions of all authors. All authors have performed the experiments together. MRG performed the hardware modifications required to the Synapt G2Si. AG performed the hardware modifications to the UV lamp. All authors have given approval to the final version of the manuscript.

ACKNOWLEDGMENT The use of tandem mass spectrometry has been shown to be a useful technique for the structural characterisation of selected PPG oligomers [1-2]. Both DPI and CID dissociation of the ammonium cationised precursor ion of poly-propylene glycol (PPG) 14-mer at m/z 848.6 was performed. Figure S5 and S6 show a comparison of the two dissociation techniques. DPI generates richer fragmentation patterns than CID, with larger diversity of fragment ions.

AG acknowledges a grant from the Idex Paris-Saclay (AAPPrematuration grant). Support from the CEPIA department of INRA and from the SOLEIL Synchrotron Radiation Facility is also greatly acknowledged.

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CONCLUSIONS Hitherto, dissociative photoionisation has been shown, using synchrotron radiation facilities, to be an efficient method of ion activation and dissociation.44,45 It has now been applied to the scale of laboratory apparatus using gas discharge photon sources in the XUV wavelength range. DPI shares common features with electron induced dissociation (EID),46 and femtosecond laser induced dissociation (fs-LID).34 EID is commercially implemented on FT-ICR instruments. fs-LID relies on fs-lasers to reach ionisation. XUV-DPI can be potentially coupled to a variety of instruments. Moreover, the photon source is inexpensive in comparison with lasers and does not require laser safety compliance. The technique advantageously complements the arsenal of available dissociation methods. XUV excitation, therefore, provides an alternative dissociation method for a wide range of singly charged small molecules and allows radical directed fragmentation for larger, predominantly singly charged species. Without further optimisation, the requirement for relatively long irradiation time makes the method incompatible with chromatography. However, we anticipate that it could provide useful structural information

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Spectrometry. Tetrahedron 2015, 71, 3039–3044. Zubarev, R. A.; Yang, H. Multiple Soft Ionization of Gas-Phase Proteins and Swift Backbone Dissociation in Collisions with ≤ 99 eV Electrons. Angew. Chemie - Int. Ed. 2010, 49 (8), 1439–

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