The combination of mass spectrometry and ion mobility spectrometry (IMS) employing a temperature-variable drift cell or a drift tube divided into sections to make IMS-IMS experiments possible allows information to be obtained about the molecular dynamics of polyatomic ions in the absence of a solvent. The experiments allow the investigation of structural changes of both activated and native ion populations on a timescale of 1–100 ms. Five different systems representing small and large, polar and nonpolar molecules, as well as noncovalent assemblies, are discussed in detail: a dinucleotide, a sodiated polyethylene glycol chain, the peptide bradykinin, the protein ubiquitin, and two types of peptide oligomers. Barriers to conformational interconversion can be obtained in favorable cases. In other cases, solution-like native structures can be observed, but care must be taken in the experimental protocols. The power of theoretical modeling is demonstrated.


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Literature Cited

  1. Walther TC, Mann M. 1.  2010. Mass spectrometry–based proteomics in cell biology. J. Cell Biol. 190:491–500 [Google Scholar]
  2. Fenn JB. 2.  2003. Electrospray wings for molecular elephants (Nobel lecture). Angew. Chem. Int. Ed. Engl. 42:3871–94 [Google Scholar]
  3. Clemmer DE, Jarrold MF. 3.  1997. Ion mobility measurements and their applications to clusters and biomolecules. J. Mass Spectrom. 32:577–92 [Google Scholar]
  4. Wyttenbach T, Bowers MT. 4.  2003. Gas-phase conformations: the ion mobility/ion chromatography method. Top. Curr. Chem. 225:207–32 [Google Scholar]
  5. Wyttenbach T, Kemper PR, Bowers MT. 5.  2001. Design of a new electrospray ion mobility mass spectrometer. Int. J. Mass Spectrom. 212:13–23 [Google Scholar]
  6. Wyttenbach T, Gidden J, Bowers MT. 6.  2011. Developments in ion mobility: theory, instrumentation, and applications. Ion Mobility Spectrometry–Mass Spectrometry CL Wilkins, S Trimpin 3–30 Boca Raton, FL: CRC [Google Scholar]
  7. Koeniger SL, Merenbloom SI, Valentine SJ, Jarrold MF, Udseth HR. 7.  et al. 2006. An IMS-IMS analogue of MS-MS. Anal. Chem. 78:4161–74 [Google Scholar]
  8. Mason EA, McDaniel EW. 8.  1988. Transport Properties of Ions in Gases New York: Wiley
  9. Wyttenbach T, Bleiholder C, Bowers MT. 9.  2013. Factors contributing to the collision cross section of polyatomic ions in the kilodalton to gigadalton range: application to ion mobility measurements. Anal. Chem. 85:2191–99 [Google Scholar]
  10. Gidden J, Bushnell JE, Bowers MT. 10.  2001. Gas-phase conformations and folding energetics of oligonucleotides: dTG and dGTP. J. Am. Chem. Soc. 123:5610–11 [Google Scholar]
  11. Gidden J, Bowers MT. 11.  2002. Gas-phase conformational and energetic properties of deprotonated dinucleotides. Eur. Phys. J. D 20:409–19 [Google Scholar]
  12. Hillenkamp F, Karas M, Beavis RC, Chait BT. 12.  1991. Matrix-assisted laser desorption/ionization mass spectrometry of biopolymers. Anal. Chem. 63:A1193–202 [Google Scholar]
  13. Tanaka K. 13.  2003. The origin of macromolecule ionization by laser irradiation (Nobel lecture). Angew. Chem. Int. Ed. Engl. 42:3860–70 [Google Scholar]
  14. Liu DF, Wyttenbach T, Bowers MT. 14.  2006. Hydration of mononucleotides. J. Am. Chem. Soc. 128:15155–63 [Google Scholar]
  15. Gatland IR. 15.  1974. Analysis for ion drift tube experiments. Case Studies in Atomic Collision Physics 4 EW McDaniel, MRC McDowell 369–437 Amsterdam: North-Holland [Google Scholar]
  16. Robinson PJ, Holbrook KA. 16.  1972. Unimolecular Reactions New York: Wiley
  17. Marcus RA, Rice OK. 17.  1951. The kinetics of the recombination of methyl radicals and iodine atoms. J. Phys. Colloid Chem. 55:894–908 [Google Scholar]
  18. Stewart JJ. 18.  1990. MOPAC: a semiempirical molecular orbital program. J. Comput. Aided Mol. Des. 4:1–105 [Google Scholar]
  19. Wyttenbach T, von Helden G, Batka JJ, Carlat D, Bowers MT. 19.  1997. Effect of the long-range potential on ion mobility measurements. J. Am. Soc. Mass Spectrom. 8:275–82 [Google Scholar]
  20. von Helden G, Wyttenbach T, Bowers MT. 20.  1995. Conformation of macromolecules in the gas phase: use of matrix-assisted laser-desorption methods in ion chromatography. Science 267:1483–85 [Google Scholar]
  21. Wyttenbach T, von Helden G, Bowers MT. 21.  1997. Conformations of alkali ion cationized polyethers in the gas phase: polyethylene glycol and bis[(benzo-15-crown-5)-15-ylmethyl] pimelate. Int. J. Mass Spectrom. 165:377–90 [Google Scholar]
  22. von Helden G, Wyttenbach T, Bowers MT. 22.  1995. Inclusion of a MALDI ion source in the ion chromatography technique: conformational information on polymer and biomolecular ions. Int. J. Mass Spectrom. Ion Process. 146:349–64 [Google Scholar]
  23. Gidden J, Wyttenbach T, Jackson AT, Scrivens JH, Bowers MT. 23.  2000. Gas-phase conformations of synthetic polymers: poly(ethylene glycol), poly(propylene glycol), and poly(tetramethylene glycol). J. Am. Chem. Soc. 122:4692–99 [Google Scholar]
  24. Jarrold MF. 24.  2000. Peptides and proteins in the vapor phase. Annu. Rev. Phys. Chem. 51:179–207 [Google Scholar]
  25. Hoadlund-Hyzer CS, Counterman AE, Clemmer DE. 25.  1999. Anhydrous protein ions. Chem. Rev. 99:3037–79 [Google Scholar]
  26. Jarrold MF. 26.  2007. Helices and sheets in vacuo. Phys. Chem. Chem. Phys. 9:1659–71 [Google Scholar]
  27. Gill AC, Jennings KR, Wyttenbach T, Bowers MT. 27.  2000. Conformations of biopolymers in the gas phase: a new mass spectrometric method. Int. J. Mass Spectrom. 196:685–97 [Google Scholar]
  28. McLean JR, McLean JA, Wu Z, Becker C, Pérez LM. 28.  et al. 2010. Factors that influence helical preferences for singly charged gas-phase peptide ions: the effects of multiple potential charge-carrying sites. J. Phys. Chem. B 114:809–16 [Google Scholar]
  29. Hudgins RR, Jarrold MF. 29.  2000. Conformations of unsolvated glycine-based peptides. J. Phys. Chem. B 104:2154–58 [Google Scholar]
  30. Kohtani M, Jones TC, Schneider JE, Jarrold MF. 30.  2004. Extreme stability of an unsolvated α-helix. J. Am. Chem. Soc. 126:7420–21 [Google Scholar]
  31. Wyttenbach T, Bushnell JE, Bowers MT. 31.  1998. Salt bridge structures in the absence of solvent? The case for the oligoglycines. J. Am. Chem. Soc. 120:5098–103 [Google Scholar]
  32. Hudgins RR, Mao Y, Ratner MA, Jarrold MF. 32.  1999. Conformations of GlynH+ and AlanH+ peptides in the gas phase. Biophys. J. 76:1591–97 [Google Scholar]
  33. Henderson SC, Li JW, Counterman AE, Clemmer DE. 33.  1999. Intrinsic size parameters for Val, Ile, Leu, Gln, Thr, Phe, and Trp residues from ion mobility measurements of polyamino acid ions. J. Phys. Chem. B 103:8780–85 [Google Scholar]
  34. Wong RL, Williams ER, Counterman AE, Clemmer DE. 34.  2005. Evaluation of ion mobility spectroscopy for determining charge-solvated versus salt-bridge structures of protonated trimers. J. Am. Soc. Mass Spectrom. 16:1009–19 [Google Scholar]
  35. Rocha e Silva M, Beraldo WT, Rosenfeld G. 35.  1949. Bradykinin, a hypotensive and smooth muscle stimulating factor released from plasma globulin by snake venoms and by trypsin. Am. J. Physiol. 156:261–73 [Google Scholar]
  36. Beraldo WT, Andrade SP. 36.  1997. Discovery of bradykinin and the kallikrein-kinin system. The Handbook of Immunopharmacology: The Kinin System SG Farmer 1–8 San Diego: Academic [Google Scholar]
  37. Wyttenbach T, von Helden G, Bowers MT. 37.  1996. Gas-phase conformation of biological molecules: bradykinin. J. Am. Chem. Soc. 118:8355–64 [Google Scholar]
  38. Schnier PD, Price WD, Jockusch RA, Williams ER. 38.  1996. Blackbody infrared radiative dissociation of bradykinin and its analogues: energetics, dynamics, and evidence for salt-bridge structures in the gas phase. J. Am. Chem. Soc. 118:7178–89 [Google Scholar]
  39. Freitas MA, Marshall AG. 39.  1999. Rate and extent of gas phase hydrogen/deuterium exchange of bradykinins: evidence for peptide zwitterions in the gas phase. Int. J. Mass Spectrom. 182–183221–31
  40. Rodriguez CF, Orlova G, Guo Y, Li X, Siu C-K. 40.  et al. 2006. Gaseous bradykinin and its singly, doubly, and triply protonated forms: a first-principles study. J. Phys. Chem. B 110:7528–37 [Google Scholar]
  41. Henderson SC, Valentine SJ, Counterman AE, Clemmer DE. 41.  1999. ESI/ion trap/ion mobility/time-of-flight mass spectrometry for rapid and sensitive analysis of biomolecular mixtures. Anal. Chem. 71:291–301 [Google Scholar]
  42. Pierson NA, Valentine SJ, Clemmer DE. 42.  2010. Evidence for a quasi-equilibrium distribution of states for bradykinin [M + 3H]3+ ions in the gas phase. J. Phys. Chem. B 114:7777–83 [Google Scholar]
  43. Pierson NA, Chen L, Valentine SJ, Russell DH, Clemmer DE. 43.  2011. Number of solution states of bradykinin from ion mobility and mass spectrometry measurements. J. Am. Chem. Soc. 133:13810–13 [Google Scholar]
  44. Lopez JJ, Shukla AK, Reinhart C, Schwalbe H, Michel H, Glaubitz C. 44.  2008. The structure of the neuropeptide bradykinin bound to the human G-protein coupled receptor bradykinin B2 as determined by solid-state NMR spectroscopy. Angew. Chem. Int. Ed. Engl. 47:1668–71 [Google Scholar]
  45. Kinnear BS, Hartings MR, Jarrold MF. 45.  2001. Helix unfolding in unsolvated peptides. J. Am. Chem. Soc. 123:5660–67 [Google Scholar]
  46. Young JK, Hicks RP. 46.  1994. NMR and molecular modeling investigations of the neuropeptide bradykinin in three different solvent systems: DMSO, 9:1 dioxane/water, and in the presence of 7.4 mM lyso phosphatidylcholine micelles. Biopolymers 34:611–23 [Google Scholar]
  47. Hicks RP. 47.  2001. Recent advances in NMR: expanding its role in rational drug design. Curr. Med. Chem. 8:627–50 [Google Scholar]
  48. Chatterjee C, Mukhopadhyay C. 48.  2004. Conformational alteration of bradykinin in presence of GM1 micelle. Biochem. Biophys. Res. Commun. 315:866–71 [Google Scholar]
  49. Lee SC, Russell AF, Laidig WD. 49.  1990. Three-dimensional structure of bradykinin in SDS micelles. Int. J. Peptide Protein Res. 35:367–77 [Google Scholar]
  50. Pierson NA, Chen L, Russell DH, Clemmer DE. 50.  2013. Cis-trans isomerizations of proline residues are key to bradykinin conformations. J. Am. Chem. Soc. 135:3186–92 [Google Scholar]
  51. Wolynes PG. 51.  1995. Biomolecular folding in vacuo!!!(?). Proc. Natl. Acad. Sci. USA 92:2426–27 [Google Scholar]
  52. Baumketner A, Bernstein SL, Wyttenbach T, Bitan G, Teplow DB. 52.  et al. 2006. Amyloid β-protein monomer structure: a computational and experimental study. Protein Sci. 15:420–28 [Google Scholar]
  53. Wyttenbach T, Bowers MT. 53.  2011. Structural stability from solution to the gas phase: Native solution structure of ubiquitin survives analysis in a solvent-free ion mobility-mass spectrometry environment. J. Phys. Chem. B 115:12266–75 [Google Scholar]
  54. Barylyuk K, Balabin RM, Grünstein D, Kikkeri R, Frankevich V. 54.  et al. 2011. What happens to hydrophobic interactions during transfer from the solution to the gas phase? The case of electrospray-based soft ionization methods. J. Am. Soc. Mass Spectrom. 22:1167–77 [Google Scholar]
  55. Ruotolo BT, Robinson CV. 55.  2006. Aspects of native proteins are retained in vacuum. Curr. Opin. Chem. Biol. 10:402–8 [Google Scholar]
  56. Barrera NP, Robinson CV. 56.  2011. Advances in the mass spectrometry of membrane proteins: from individual proteins to intact complexes. Annu. Rev. Biochem. 80:247–71 [Google Scholar]
  57. Vijay-Kumar S, Bugg CE, Cook WJ. 57.  1987. Structure of ubiquitin refined at 1.8 Å resolution. J. Mol. Biol. 194:531–44 [Google Scholar]
  58. Brutscher B, Bruschweiler R, Ernst RR. 58.  1997. Backbone dynamics and structural characterization of the partially folded A state of ubiquitin by 1H, 13C, and 15N nuclear magnetic resonance spectroscopy. Biochemistry 36:13043–53 [Google Scholar]
  59. Chowdhury SK, Katta V, Chait BT. 59.  1990. Probing conformational changes in proteins by mass spectrometry. J. Am. Chem. Soc. 112:9012–13 [Google Scholar]
  60. Katta V, Chait BT. 60.  1991. Conformational changes in proteins probed by hydrogen-exchange electrospray-ionization mass spectrometry. Rapid Commun. Mass Spectrom. 5:214–17 [Google Scholar]
  61. Konermann L, Douglas DJ. 61.  1998. Unfolding of proteins monitored by electrospray ionization mass spectrometry: a comparison of positive and negative ion modes. J. Am. Soc. Mass Spectrom. 9:1248–54 [Google Scholar]
  62. Clemmer DE, Hudgins RR, Jarrold MF. 62.  1995. Naked protein conformations: cytochrome c in the gas phase. J. Am. Chem. Soc. 117:10141–42 [Google Scholar]
  63. Valentine SJ, Anderson JG, Ellington AD, Clemmer DE. 63.  1997. Disulfide-intact and -reduced lysozyme in the gas phase: conformations and pathways of folding and unfolding. J. Phys. Chem. B 101:3891–900 [Google Scholar]
  64. Shelimov KB, Jarrold MF. 64.  1997. Conformations, unfolding, and refolding of apomyoglobin in vacuum: an activation barrier for gas-phase protein folding. J. Am. Chem. Soc. 119:2987–94 [Google Scholar]
  65. Wilson DJ, Konermann L. 65.  2003. A capillary mixer with adjustable reaction chamber volume for millisecond time-resolved studies by electrospray mass spectrometry. Anal. Chem. 75:6408–14 [Google Scholar]
  66. Valentine SJ, Counterman AE, Clemmer DE. 66.  1997. Conformer-dependent proton-transfer reactions of ubiquitin ions. J. Am. Soc. Mass Spectrom. 8:954–61 [Google Scholar]
  67. Myung S, Badman ER, Lee YJ, Clemmer DE. 67.  2002. Structural transitions of electrosprayed ubiquitin ions stored in an ion trap over ∼10 ms to 30 s. J. Phys. Chem. A 106:9976–82 [Google Scholar]
  68. Shvartsburg AA, Jarrold MF. 68.  1996. An exact hard-spheres scattering model for the mobilities of polyatomic ions. Chem. Phys. Lett. 261:86–91 [Google Scholar]
  69. Steinberg MZ, Elber R, McLafferty FW, Gerber RB, Breuker K. 69.  2008. Early structural evolution of native cytochrome c after solvent removal. Chembiochem 9:2417–23 [Google Scholar]
  70. Koeniger SL, Merenbloom SI, Clemmer DE. 70.  2006. Evidence for many resolvable structures within conformation types of electrosprayed ubiquitin ions. J. Phys. Chem. B 110:7017–21 [Google Scholar]
  71. Koeniger SL, Merenbloom SI, Sevugarajan S, Clemmer DE. 71.  2006. Transfer of structural elements from compact to extended states in unsolvated ubiquitin. J. Am. Chem. Soc. 128:11713–19 [Google Scholar]
  72. Shi H, Pierson NA, Valentine SJ, Clemmer DE. 72.  2012. Conformation types of ubiquitin [M+8H]8+ ions from water:methanol solutions: evidence for the N and A states in aqueous solution. J. Phys. Chem. B 116:3344–52 [Google Scholar]
  73. Segev E, Wyttenbach T, Bowers MT, Gerber RB. 73.  2008. Conformational evolution of ubiquitin ions in electrospray mass spectrometry: molecular dynamics simulations at gradually increasing temperatures. Phys. Chem. Chem. Phys. 10:3077–82 [Google Scholar]
  74. Koeniger SL, Clemmer DE. 74.  2007. Resolution and structural transitions of elongated states of ubiquitin. J. Am. Soc. Mass Spectrom. 18:322–31 [Google Scholar]
  75. Park AY, Robinson CV. 75.  2011. Protein–nucleic acid complexes and the role of mass spectrometry in their structure determination. Crit. Rev. Biochem. Mol. 46:152–64 [Google Scholar]
  76. Hyung SJ, Ruotolo BT. 76.  2012. Integrating mass spectrometry of intact protein complexes into structural proteomics. Proteomics 12:1547–64 [Google Scholar]
  77. Uetrecht C, Rose RJ, van Duijn E, Lorenzen K, Heck AJR. 77.  2010. Ion mobility mass spectrometry of proteins and protein assemblies. Chem. Soc. Rev. 39:1633–55 [Google Scholar]
  78. Wyttenbach T, Bowers MT. 78.  2007. Intermolecular interactions in biomolecular systems examined by mass spectrometry. Annu. Rev. Phys. Chem. 58:511–33 [Google Scholar]
  79. Teplow DB, Lazo ND, Bitan G, Bernstein S, Wyttenbach T. 79.  et al. 2006. Elucidating amyloid β-protein folding and assembly: a multidisciplinary approach. Acc. Chem. Res. 39:635–45 [Google Scholar]
  80. Bernstein SL, Dupuis NF, Lazo ND, Wyttenbach T, Condron MM. 80.  et al. 2009. Amyloid-β protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer's disease. Nat. Chem. 1:326–31 [Google Scholar]
  81. Bleiholder C, Dupuis NF, Wyttenbach T, Bowers MT. 81.  2011. Ion mobility–mass spectrometry reveals a conformational conversion from random assembly to β-sheet in amyloid fibril formation. Nat. Chem. 3:172–77 [Google Scholar]
  82. Kirkitadze MD, Bitan G, Teplow DB. 82.  2002. Paradigm shifts in Alzheimer's disease and other neurodegenerative disorders: the emerging role of oligomeric assemblies. J. Neurosci. Res. 69:567–77 [Google Scholar]
  83. Deschamps JR, George C, Flippen-Anderson JL. 83.  1996. Structural studies of opioid peptides: a review of recent progress in X-ray diffraction studies. Biopolymers 40:121–39 [Google Scholar]
  84. Smith GD, Griffin JF. 84.  1978. Conformation of [Leu5]enkephalin from X-ray diffraction: features important for recognition at opiate receptor. Science 199:1214–16 [Google Scholar]
  85. DePace AH, Santoso A, Hillner P, Weissman JS. 85.  1998. A critical role for amino-terminal glutamine/asparagine repeats in the formation and propagation of a yeast prion. Cell 93:1241–52 [Google Scholar]
  86. Prusiner SB. 86.  1998. Prions. Proc. Natl. Acad. Sci. USA 95:13363–83 [Google Scholar]
  87. Balbirnie M, Grothe R, Eisenberg DS. 87.  2001. An amyloid-forming peptide from the yeast prion Sup35 reveals a dehydrated β-sheet structure for amyloid. Proc. Natl. Acad. Sci. USA 98:2375–80 [Google Scholar]
  88. Nelson R, Sawaya MR, Balbirnie M, Madsen AO, Riekel C. 88.  et al. 2005. Structure of the cross-β spine of amyloid-like fibrils. Nature 435:773–78 [Google Scholar]

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