Rapid Solution-Phase Hydrogen/Deuterium Exchange for Metabolite Compound Identification

  • Sandra N. Majuta
  • Chong Li
  • Kinkini Jayasundara
  • Ahmad Kiani Karanji
  • Kushani Attanayake
  • Nandhini Ranganathan
  • Peng Li
  • Stephen J. ValentineEmail author
Focus: Ion Mobility Spectrometry (IMS): Research Article


Rapid, solution-phase hydrogen/deuterium exchange (HDX) coupled with mass spectrometry (MS) is demonstrated as a means for distinguishing small-molecule metabolites. HDX is achieved using capillary vibrating sharp-edge spray ionization (cVSSI) to allow sufficient time for reagent mixing and exchange in micrometer-sized droplets. Different compounds are observed to incorporate deuterium with varying efficiencies resulting in unique isotopic patterns as revealed in the MS spectra. Using linear regression techniques, parameters representing contribution to exchange by different hydrogen types can be computed. In this proof-of-concept study, the exchange parameters are shown to be useful in the retrodiction of the amount of deuterium incorporated within different compounds. On average, the exchange parameters retrodict the exchange level with ~ 2.2-fold greater accuracy than treating all exchangeable hydrogens equally. The parameters can be used to produce hypothetical isotopic distributions that agree (± 16% RMSD) with experimental measurements. These initial studies are discussed in light of their potential value for identifying challenging metabolite species.


Metabolomics Hydrogen-deuterium exchange Compound identification 



We are grateful for financial support from the National Science Foundation (CHE-1553021).

Supplementary material

13361_2019_2163_MOESM1_ESM.docx (296 kb)
ESM 1 (DOCX 295 kb)


  1. 1.
    Ceglarek, U., Leichtle, A., Brugel, M., Kortz, L., Brauer, R., Bresler, K., Thiery, J., Fiedler, G.M.: Challenges and developments in tandem mass spectrometry based clinical metabolomics. Mol. Cell. Endocrinol. 301, 266–271 (2009)CrossRefGoogle Scholar
  2. 2.
    Welthagen, W., Shellie, R.A., Spranger, J., Ristow, M., Zimmermann, R., Fiehn, O.: Comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (GC × GC-TOF) for high resolution metabolomics: biomarker discovery on spleen tissue extracts of obese NZO compared to lean C57BL/6 mice. Metabolomics. 1, 65–73 (2005)CrossRefGoogle Scholar
  3. 3.
    Peng, B., Li, H., Peng, X.X.: Functional metabolomics: from biomarker discovery to metabolome reprogramming. Protein Cell. 6, 628–637 (2015)CrossRefGoogle Scholar
  4. 4.
    Vizcaino, M.I., Engel, P., Trautman, E., Crawford, J.M.: Comparative metabolomics and structural characterizations illuminate colibactin pathway-dependent small molecules. J. Am. Chem. Soc. 136, 9244–9247 (2014)CrossRefGoogle Scholar
  5. 5.
    Chaleckis, R., Murakami, I., Takada, J., Kondoh, H., Yanagida, M.: Individual variability in human blood metabolites identifies age-related differences. Proc. Natl. Acad. Sci. U. S. A. 113, 4252–4259 (2016)CrossRefGoogle Scholar
  6. 6.
    Blum, B.C., Mousavi, F., Emili, A.: Single-platform “multi-omic” profiling: unified mass spectrometry and computational workflows for integrative proteomics-metabolomics analysis. Mol Omics. 14, 307–319 (2018)CrossRefGoogle Scholar
  7. 7.
    Abbondante, S., Eckel-Mahan, K.L., Ceglia, N.J., Baldi, P., Sassone-Corsi, P.: Comparative circadian metabolomics reveal differential effects of nutritional challenge in the serum and liver. J. Biol. Chem. 291, 2812–2828 (2016)CrossRefGoogle Scholar
  8. 8.
    Jove, M., Portero-Otin, M., Naudi, A., Ferrer, I., Pamplona, R.: Metabolomics of human brain aging and age-related neurodegenerative diseases. J. Neuropathol. Exp. Neurol. 73, 640–657 (2014)CrossRefGoogle Scholar
  9. 9.
    Gibb, A.A., Hill, B.G.: Metabolic coordination of physiological and pathological cardiac remodeling. Circ. Res. 123, 107–128 (2018)CrossRefGoogle Scholar
  10. 10.
    Vohra, A., Asnani, A.: Biomarker discovery in cardio-oncology. Cur. Cardiol. Rep. 20, 8 (2018)CrossRefGoogle Scholar
  11. 11.
    Chen, Z.D., Zhang, Y.S., Vouros, P.: Recent technical and biological development in the analysis of biomarker N-deoxyguanosine-C8-4-aminobiphenyl. J. Chromatogr. B. 1087, 49–60 (2018)CrossRefGoogle Scholar
  12. 12.
    Maleki, H., Karanji, A.K., Majuta, S., Maurer, M.M., Valentine, S.J.: Ion mobility spectrometry-mass spectrometry coupled with gas-phase hydrogen/deuterium exchange for metabolomics analyses. J. Am. Soc. Mass Spectrom. 29, 230–241 (2018)CrossRefGoogle Scholar
  13. 13.
    Lee, S.H., Kim, S.O., Lee, H.D., Chung, B.C.: Estrogens and polyamines in breast cancer: their profiles and values in disease staging. Cancer Lett. 133, 47–56 (1998)CrossRefGoogle Scholar
  14. 14.
    Wang, B., Valentine, S., Plasencia, M., Raghuraman, S., Zhang, X.A.: Artificial neural networks for the prediction of peptide drift time in ion mobility mass spectrometry. BMC Bioinform. 11, 11 (2010)CrossRefGoogle Scholar
  15. 15.
    Johnson, C.H., Ivanisevic, J., Siuzdak, G.: Metabolomics: beyond biomarkers and towards mechanisms. Nat. Rev. Mol. Cell Biol. 17, 451–459 (2016)CrossRefGoogle Scholar
  16. 16.
    Shahrjooihaghighi, A., Frigui, H., Zhang, X., Wei, X.L., Shi, B.Y., Trabelsi, A.: An ensemble feature selection method for biomarker discovery, pp. 416–421. 2017 IEEE International Symposium on Signal Processing and Information Technology, IEEE, New York (2017)Google Scholar
  17. 17.
    Hao, L., Wang, J.X., Page, D., Asthana, S., Zetterberg, H., Carlsson, C., Okonkwo, O.C., Li, L.J.: Comparative evaluation of MS-based metabolomics software and its application to preclinical Alzheimer’s disease. Sci. Rep. 8, 10 (2018)CrossRefGoogle Scholar
  18. 18.
    Hao, L., Johnson, J., Lietz, C.B., Buchberger, A., Frost, D., Kao, W.J., Li, L.J.: Mass defect-based N,N-dimethyl leucine labels for quantitative proteomics and amine metabolomics of pancreatic cancer cells. Anal. Chem. 89, 1138–1146 (2017)CrossRefGoogle Scholar
  19. 19.
    Johnson, C.H., Gonzalez, F.J.: Challenges and opportunities of metabolomics. J. Cell. Physiol. 227, 2975–2981 (2012)CrossRefGoogle Scholar
  20. 20.
    Tang, Y., Wei, J., Costello, C.E., Lin, C.: Characterization of isomeric glycans by reversed phase liquid chromatography-electronic excitation dissociation tandem mass spectrometry. J. Am. Soc. Mass Spectrom. 29, 1295–1307 (2018)CrossRefGoogle Scholar
  21. 21.
    Sinclair, E., Hollywood, K.A., Yan, C.Y., Blankley, R., Breitling, R., Barran, P.: Mobilising ion mobility mass spectrometry for metabolomics. Analyst. 143, 4783–4788 (2018)CrossRefGoogle Scholar
  22. 22.
    Dettmer, K., Aronov, P.A., Hammock, B.D.: Mass spectrometry-based metabolomics. Mass Spectrom. Rev. 26, 51–78 (2007)CrossRefGoogle Scholar
  23. 23.
    Mirnaghi, F.S., Caudy, A.A.: Challenges of analyzing different classes of metabolites by a single analytical method. Bioanalysis. 6, 3393–3416 (2014)CrossRefGoogle Scholar
  24. 24.
    Wishart, D.S., Feunang, Y.D., Marcu, A., Guo, A.C., Liang, K., Vazquez-Fresno, R., Sajed, T., Johnson, D., Li, C., Karu, N., Sayeeda, Z., Lo, E., Assempour, N., Berjanskii, M., Singhal, S., Arndt, D., Liang, Y., Badran, H., Grant, J., Serra-Cayuela, A., Liu, Y., Mandal, R., Neveu, V., Pon, A., Knox, C., Wilson, M., Manach, C., Scalbert, A.: HMDB 4.0: the human metabolome database for 2018. Nucleic Acids Res. 46, D608–D617 (2018)CrossRefGoogle Scholar
  25. 25.
    Gooch, C.L., Pracht, E., Borenstein, A.R.: The burden of neurological disease in the United States: a summary report and call to action. Ann. Neurol. 81, 479–484 (2017)CrossRefGoogle Scholar
  26. 26.
    Dai, W.D., Yin, P.Y., Zeng, Z.D., Kong, H.W., Tong, H.W., Xu, Z.L., Lu, X., Lehmann, R., Xu, G.W.: Nontargeted modification-specific metabolomics study based on liquid chromatography high-resolution mass spectrometry. Anal. Chem. 86, 9146–9153 (2014)CrossRefGoogle Scholar
  27. 27.
    Forcisi, S., Moritz, F., Kanawati, B., Tziotis, D., Lehmann, R., Schmitt-Kopplin, P.: Liquid chromatography-mass spectrometry in metabolomics research: mass analyzers in ultra-high pressure liquid chromatography coupling. J. Chromatogr. A. 1292, 51–65 (2013)CrossRefGoogle Scholar
  28. 28.
    Kohler, I., Giera, M.: Recent advances in liquid-phase separations for clinical metabolomics. J. Sep. Sci. 40, 93–108 (2017)CrossRefGoogle Scholar
  29. 29.
    Palagama, D.S.W., Baliu-Rodriguez, D., Lad, A., Levison, B.S., Kennedy, D.J., Hailer, S.T., Westrick, J., Hensley, K., Isailovic, D.: Development and applications of solid-phase extraction and liquid chromatography-mass spectrometry methods for quantification of microcystins in urine, plasma, and serum. J. Chromatogr. A. 1573, 66–77 (2018)CrossRefGoogle Scholar
  30. 30.
    Ibanez, C., Simo, C., Palazoglu, M., Cifuentes, A.: GC-MS based metabolomics of colon cancer cells using different extraction solvents. Anal. Chim. Acta. 986, 48–56 (2017)CrossRefGoogle Scholar
  31. 31.
    Myers, O.D., Sumner, S.J., Li, S.Z., Barnes, S., Du, X.X.: One step forward for reducing false positive and false negative compound identifications from mass spectrometry metabolomics data: new algorithms for constructing extracted ion chromatograms and detecting chromatographic peaks. Anal. Chem. 89, 8696–8703 (2017)CrossRefGoogle Scholar
  32. 32.
    Koo, I., Kim, S., Shi, B.Y., Lorkiewicz, P., Song, M., McClain, C., Zhang, X.: EIder: a compound identification tool for gas chromatography mass spectrometry data. J. Chromatogr. A. 1448, 107–114 (2016)CrossRefGoogle Scholar
  33. 33.
    Koo, I., Shi, X., Kim, S., Zhang, X.: iMatch2: compound identification using retention index for analysis of gas chromatography-mass spectrometry data. J. Chromatogr. A. 1337, 202–210 (2014)CrossRefGoogle Scholar
  34. 34.
    Singh, V., Sharma, R.K., Athilingam, T., Sinha, P., Sinha, N., Thakur, A.K.: NMR spectroscopy-based metabolomics of Drosophila model of Huntington's disease suggests altered cell energetics. J. Proteome Res. 16, 3863–3872 (2017)CrossRefGoogle Scholar
  35. 35.
    Gerbst, A.G., Nikolaev, A.V., Yashunsky, D.V., Shashkov, A.S., Dmitrenok, A.S., Nifantiev, N.E.: Theoretical and NMR-based conformational analysis of phosphodiester-linked disaccharides. Sci. Rep. 7, 9 (2017)CrossRefGoogle Scholar
  36. 36.
    Brindle, J.T., Antti, H., Holmes, E., Tranter, G., Nicholson, J.K., Bethell, H.W.L., Clarke, S., Schofield, P.M., McKilligin, E., Mosedale, D.E., Grainger, D.J.: Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics. Nat. Med. 9, 477–477 (2003)CrossRefGoogle Scholar
  37. 37.
    Cheng, L.L., Burns, M.A., Taylor, J.L., He, W.L., Halpern, E.F., McDougal, W.S., Wu, C.L.: Metabolic characterization of human prostate cancer with tissue magnetic resonance spectroscopy. Cancer Res. 65, 3030–3034 (2005)CrossRefGoogle Scholar
  38. 38.
    Kirschenlohr, H.L., Griffin, J.L., Clarke, S.C., Rhydwen, R., Grace, A.A., Schofield, P.M., Brindle, K.M., Metcalfe, J.C.: Proton NMR analysis of plasma is a weak predictor of coronary artery disease. Nat. Med. 12, 862–862 (2006)CrossRefGoogle Scholar
  39. 39.
    Fiehn, O., Garvey, W.T., Newman, J.W., Lok, K.H., Hoppel, C.L., Adams, S.H.: Plasma metabolomic profiles reflective of glucose homeostasis in non-diabetic and type 2 diabetic obese African-American women. PLoS One. 5, 10 (2010)CrossRefGoogle Scholar
  40. 40.
    Patterson, A.D., Bonzo, J.A., Li, F., Krausz, K.W., Eichler, G.S., Aslam, S., Tigno, X., Weinstein, J.N., Hansen, B.C., Idle, J.R., Gonzalez, F.J.: Metabolomics reveals attenuation of the SLC6A20 kidney transporter in nonhuman primate and mouse models of type 2 diabetes mellitus. J. Biol. Chem. 286, 19511–19522 (2011)CrossRefGoogle Scholar
  41. 41.
    Arn, P.H.: Newborn screening: current status. Health Aff. 26, 559–566 (2007)CrossRefGoogle Scholar
  42. 42.
    Wikoff, W.R., Gangoiti, J.A., Barshop, B.A., Siuzdak, G.: Metabolomics identifies perturbations in human disorders of propionate metabolism. Clin. Chem. 53, 2169–2176 (2007)CrossRefGoogle Scholar
  43. 43.
    Manna, S.K., Patterson, A.D., Yang, Q., Krausz, K.W., Idle, J.R., Fornace, A.J., Gonzalez, F.J.: UPLC-MS-based urine metabolomics reveals Indole-3-lactic acid and phenyllactic acid as conserved biomarkers for alcohol-induced liver disease in the Ppara-null mouse model. J. Proteome Res. 10, 4120–4133 (2011)CrossRefGoogle Scholar
  44. 44.
    Manna, S.K., Patterson, A.D., Yang, Q.A., Krausz, K.W., Li, H.H., Idle, J.R., Fornace, A.J., Gonzalez, F.J.: Identification of noninvasive biomarkers for alcohol-induced liver disease using urinary metabolomics and the Ppara-null mouse. J. Proteome Res. 9, 4176–4188 (2010)CrossRefGoogle Scholar
  45. 45.
    Koh, P., Chan, E., Mal, M., Eu, K., Blackshall, A., Keun, H.: Metabolic profiling of human colorectal cancer using high-resolution magic angle spinning nuclear magnetic resonance (HR-MAS NMR) spectroscopy and gas chromatography mass spectrometry (GC/MS). Dis. Colon Rectum. 52, 769–769 (2009)CrossRefGoogle Scholar
  46. 46.
    Stolarczyka, E.U., Rosa, A., Kubiszewski, M., Zagrodzka, J., Cybulski, M., Kaczmarek, L.: Use of the hyphenated LC-MS/MS technique and NMR/IR spectroscopy for the identification of exemestane stress degradation products during the drug development. Eur. J. Pharm. Sci. 109, 389–401 (2017)CrossRefGoogle Scholar
  47. 47.
    National Institutes of Health, Compound identification development cores, 17 November 2018. Accessed 17 Nov 2018
  48. 48.
    Giddings, J.C.: Two-dimensional separations—concept and promise. Anal. Chem. 56, 1258 (1984)CrossRefGoogle Scholar
  49. 49.
    Fetterolf, D.D., Yost, R.A.: Added resolution elements for greater informing power in tandem mass-spectrometry. Int. J. Mass Spectrom. Ion Process. 62, 33–49 (1984)CrossRefGoogle Scholar
  50. 50.
    Bantscheff, M., Schirle, M., Sweetman, G., Rick, J., Kuster, B.: Quantitative mass spectrometry in proteomics: a critical review. Anal. Bioanal. Chem. 389, 1017–1031 (2007)CrossRefGoogle Scholar
  51. 51.
    Freund, D.M., Hegeman, A.D.: Recent advances in stable isotope-enabled mass spectrometry-based plant metabolomics. Curr. Opin. Biotechnol. 43, 41–48 (2017)CrossRefGoogle Scholar
  52. 52.
    Mahieu, N.G., Genenbacher, J.L., Patti, G.J.: A roadmap for the XCMS family of software solutions in metabolomics. Curr. Opin. Chem. Biol. 30, 87–93 (2016)CrossRefGoogle Scholar
  53. 53.
    Wotherspoon, A.T.L., Safavi-Naeini, M., Banati, R.B.: Microdosing, isotopic labeling, radiotracers and metabolomics: relevance in drug discovery, development and safety. Bioanalysis. 9, 1913–1933 (2017)CrossRefGoogle Scholar
  54. 54.
    Luo, X., An, M.R., Cuneo, K.C., Lubman, D.M., Li, L.: High-performance chemical isotope labeling liquid chromatography mass spectrometry for exosome metabolomics. Anal. Chem. 90, 8314–8319 (2018)CrossRefGoogle Scholar
  55. 55.
    Wei, X.L., Shi, B.Y., Koo, I., Yin, X.M., Lorkiewicz, P., Suhail, H., Rattan, R., Giri, S., McClain, C.J., Zhang, X.: Analysis of stable isotope assisted metabolomics data acquired by GC-MS. Anal. Chim. Acta. 980, 25–32 (2017)CrossRefGoogle Scholar
  56. 56.
    Dugourd, P., Hudgins, R.R., Clemmer, D.E., Jarrold, M.F.: High-resolution ion mobility measurements. Rev. Sci. Instrum. 68, 1122–1129 (1997)CrossRefGoogle Scholar
  57. 57.
    Dwivedi, P., Schultz, A.J., Hill, H.H.: Metabolic profiling of human blood by high-resolution ion mobility mass spectrometry (IM-MS). Int. J. Mass Spectrom. 298, 78–90 (2010)CrossRefGoogle Scholar
  58. 58.
    Fenn, L.S., Kliman, M., Mahsut, A., Zhao, S.R., McLean, J.A.: Characterizing ion mobility-mass spectrometry conformation space for the analysis of complex biological samples. Anal. Bioanal. Chem. 394, 235–244 (2009)CrossRefGoogle Scholar
  59. 59.
    Donohoe, G.C., Maleki, H., Arndt, J.R., Khakinejad, M., Yi, J., McBride, C., Nurkiewicz, T.R., Valentine, S.J.: A new ion mobility-linear ion trap instrument for complex mixture analysis. Anal. Chem. 86, 8121–8128 (2014)CrossRefGoogle Scholar
  60. 60.
    Chouinard, C.D., Beekman, C.R., Kemperman, R.H.J., King, H.M., Yost, R.A.: Ion mobility-mass spectrometry separation of steroid structural isomers and epimers. Int. J. Ion Mobil. Spectrom. 20, 31–39 (2017)CrossRefGoogle Scholar
  61. 61.
    Chouinard, C.D., Wei, M.S., Beekman, C.R., Kemperman, R.H.J., Yost, R.A.: Ion mobility in clinical analysis: current progress and future perspectives. Clin. Chem. 62, 124–133 (2016)CrossRefGoogle Scholar
  62. 62.
    Ibrahim, Y.M., Baker, E.S., Danielson, W.F., Norheim, R.V., Prior, D.C., Anderson, G.A., Belov, M.E., Smith, R.D.: Development of a new ion mobility (quadrupole) time-of-flight mass spectrometer. Int. J. Mass Spectrom. 377, 655–662 (2015)CrossRefGoogle Scholar
  63. 63.
    Kyle, J.E., Zhang, X., Weitz, K.K., Monroe, M.E., Ibrahim, Y.M., Moore, R.J., Cha, J., Sun, X.F., Lovelace, E.S., Wagoner, J., Polyak, S.J., Metz, T.O., Dey, S.K., Smith, R.D., Burnum-Johnson, K.E., Baker, E.S.: Uncovering biologically significant lipid isomers with liquid chromatography, ion mobility spectrometry and mass spectrometry. Analyst. 141, 1649–1659 (2016)CrossRefGoogle Scholar
  64. 64.
    Crowell, K.L., Slysz, G.W., Baker, E.S., LaMarche, B.L., Monroe, M.E., Ibrahim, Y., Payne, S.H., Anderson, G.A., Smith, R.D.: LC-IMS-MS Feature Finder: detecting multidimensional liquid chromatography, ion mobility and mass spectrometry features in complex datasets. Bioinformatics. 29, 2804–2805 (2013)CrossRefGoogle Scholar
  65. 65.
    Lareau, N.M., May, J.C., McLean, J.A.: Non-derivatized glycan analysis by reverse phase liquid chromatography and ion mobility-mass spectrometry. Analyst. 140, 3335–3338 (2015)CrossRefGoogle Scholar
  66. 66.
    Hoaglund-Hyzer, C.S., Li, J.W., Clemmer, D.E.: Mobility labeling for parallel CID of ion mixtures. Anal. Chem. 72, 2737–2740 (2000)CrossRefGoogle Scholar
  67. 67.
    Liu, D.Q., Hop, C., Beconi, M.G., Mao, A., Chiu, S.H.L.: Use of on-line hydrogen/deuterium exchange to facilitate metabolite identification. Rapid Comm. Mass Spectrom. 15, 1832–1839 (2001)CrossRefGoogle Scholar
  68. 68.
    Ohashi, N., Furuuchi, S., Yoshikawa, M.: Usefulness of the hydrogen-deuterium exchange method in the study of drug metabolism using liquid chromatography tandem mass spectrometry. J. Pharm. Biomed. Anal. 18, 325–334 (1998)CrossRefGoogle Scholar
  69. 69.
    Khakinejad, M., Kondalaji, S.G., Maleki, H., Arndt, J.R., Donohoe, G.C., Valentine, S.J.: Combining ion mobility spectrometry with hydrogen-deuterium exchange and top-down MS for peptide ion structure analysis. J. Am. Soc. Mass Spectrom. 25, 2103–2115 (2014)CrossRefGoogle Scholar
  70. 70.
    Uppal, S.S., Beasley, S.E., Scian, M., Guttman, M.: Gas-phase hydrogen/deuterium exchange for distinguishing isomeric carbohydrate ions. Anal. Chem. 89, 4737–4742 (2017)CrossRefGoogle Scholar
  71. 71.
    Lam, W., Ramanathan, R.: In electrospray ionization source hydrogen/deuterium exchange LC-MS and LC-MS/MS for characterization of metabolites. J. Am. Soc. Mass Spectrom. 13, 345–353 (2002)CrossRefGoogle Scholar
  72. 72.
    Valentine, S.J., Counterman, A.E., Clemmer, D.E.: A database of 660 peptide ion cross sections: use of intrinsic size parameters for bona fide predictions of cross sections. J. Am. Soc. Mass Spectrom. 10, 1188–1211 (1999)CrossRefGoogle Scholar
  73. 73.
    Shvartsburg, A.A., Siu, K.W.M., Clemmer, D.E.: Prediction of peptide ion mobilities via a priori calculations from intrinsic size parameters of amino acid residues. J. Am. Soc. Mass Spectrom. 12, 885–888 (2001)CrossRefGoogle Scholar
  74. 74.
    Dodds, J.N., May, J.C., McLean, J.A.: Investigation of the complete suite of the leucine and isoleucine isomers: toward prediction of ion mobility separation capabilities. Anal. Chem. 89, 952–959 (2017)CrossRefGoogle Scholar
  75. 75.
    Mark, L.P., Gill, M.C., Mahut, M., Derrick, P.J.: Dual nano-electrospray for probing solution interactions and fast reactions of complex biomolecules. Eur. J. Mass Spectrom. 18, 439–446 (2012)CrossRefGoogle Scholar
  76. 76.
    Mortensen, D.N., Williams, E.R.: Theta-glass capillaries in electrospray ionization: rapid mixing and short droplet lifetimes. Anal. Chem. 86, 9315–9321 (2014)CrossRefGoogle Scholar
  77. 77.
    Mortensen, D.N., Williams, E.R.: Investigating protein folding and unfolding in electrospray nanodrops upon rapid mixing using Theta-glass emitters. Anal. Chem. 87, 1281–1287 (2015)CrossRefGoogle Scholar
  78. 78.
    Arscott, S., Gaudet, M., Brinkmann, M., Ashcroft, A.E., Blossey, R.: Capillary filling of miniaturized sources for electrospray mass spectrometry. J. Phys. Condens Matter. 18, S677–S690 (2006)CrossRefGoogle Scholar
  79. 79.
    Jansson, E.T., Lai, Y.H., Santiago, J.G., Zare, R.N.: Rapid hydrogen-deuterium exchange in liquid droplets. J. Am. Chem. Soc. 139, 6851–6854 (2017)CrossRefGoogle Scholar
  80. 80.
    Li, X., Attanayake, K., Valentine, S.J., Li, P.: Vibrating sharp-edge spray ionisation VSSI. Rapid Commun. Mass Spectrom. (2018).
  81. 81.
    Ranganathan, N., Suder, T., Kiani Karanji, A., Li, X., He, Z., Valentine, S. J., Li, P. Capillary-based vibrating sharp-edge spray ionisation (cVSSI) for voltage-free liquid chromatography-mass spectrometry. J. Am. Soc. Mass Spectrom. (submitted)Google Scholar
  82. 82.
    Konermann, L.: Addressing a common misconception: ammonium acetate as neutral pH “buffer” for native electrospray mass spectrometry. J. Am. Soc. Mass Spectrom. 28, 1827–1835 (2017)CrossRefGoogle Scholar
  83. 83.
    Counterman, A.E., Clemmer, D.E.: Volumes of individual amino acid residues in gas-phase peptide ions. J. Am. Chem. Soc. 121, 4031–4039 (1999)CrossRefGoogle Scholar
  84. 84.
    Englander, S.W., Sosnick, T.R., Englander, J.J., Mayne, L.: Mechanisms and uses of hydrogen exchange. Curr. Opin. Struct. Biol. 6, 18–23 (1996)CrossRefGoogle Scholar
  85. 85.
    Englander, S.W., Kallenbach, N.R.: Hydrogen-exchange and structural dynamics of proteins and nucleic-acids. Q. Rev. Biophys. 16, 521–655 (1983)CrossRefGoogle Scholar
  86. 86.
    Bai, Y., Sosnick, T.R., Mayne, L., Englander, S.W.: Protein-folding intermediates by native hydrogen-exchange. FASEB J. 9, A1239–A1239 (1995)Google Scholar
  87. 87.
    Wishart, D.S., Jewison, T., Guo, A.C., Wilson, M., Knox, C., Liu, Y.F., Djoumbou, Y., Mandal, R., Aziat, F., Dong, E., Bouatra, S., Sinelnikov, I., Arndt, D., Xia, J.G., Liu, P., Yallou, F., Bjorndahl, T., Perez-Pineiro, R., Eisner, R., Allen, F., Neveu, V., Greiner, R., Scalbert, A.: HMDB 3.0—the human metabolome database. Nucleic Acids Res. 41, D801–D807 (2013)CrossRefGoogle Scholar
  88. 88.
    Liepinsh, E., Otting, G.: Proton exchange rates from amino acid side chains—implications for image contrast. Magn. Res. Med. 35, 30–42 (1996)CrossRefGoogle Scholar
  89. 89.
    Engen, J. R.: Hydrogen exchange mass spectrometry: methods, 21 2018. Accessed 17 Nov 2018

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© American Society for Mass Spectrometry 2019

Authors and Affiliations

  1. 1.C. Eugene Bennett Department of ChemistryWest Virginia UniversityMorgantownUSA

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