Structure of Nucleic Acids in the Gas Phase

  • Annalisa Arcella
  • Guillem Portella
  • Modesto OrozcoEmail author
Part of the Physical Chemistry in Action book series (PCIA)


Evolution has refined nucleic acids to display well-defined three-dimensional structures that are functional under aqueous physiological conditions. While the structure of nucleic acids is well known in solution, it is unclear how nucleic acids react when transferred to a fully anhydrous environment. Simple physical chemistry considerations suggest that a heavily charged poly-anion would adopt fully extended conformations in vacuum, and that multistranded structure would dissociate, to guarantee that charged residues separate as much as possible to reduce Coulomb repulsion. However, and quite counterintuitively, a vast amount of experiments demonstrate that this is not the case and that oligomeric nucleic acids adopt quite compact structures in the gas phase, which in some cases might preserve memories of the original conformation in solution. In this chapter, we review our current understanding of nucleic acid structure in the gas phase.


Nucleic acids Gas phase Electrospray Soft Ionization Mass spectrometry Molecular dynamics Ion mobility spectrometry DNA Simulation 



Electrospray soft ionization mass spectrometry


Ion mobility spectrometry


In vacuum native structure


X-ray free electron laser


Collision cross section


Molecular dynamics


Quantum mechanics


Density functional theory


Coupled cluster with single, double, and triple excitation/complete basis set


  1. 1.
    Blackburn GM, Gait MJ (1990) Nucleic acids in chemistry and biology. IRL Press, OxfordGoogle Scholar
  2. 2.
    Bloomfield VA, Crothers DM, Tinoco I (2000) Nucleic acids. Structure, properties and functions. University Science, Sausalito, CAGoogle Scholar
  3. 3.
    Saenger W (1984) Principles of nucleic acid structure. Springer, New York, NYCrossRefGoogle Scholar
  4. 4.
    Sinden RR (1994) DNA structure and function. Academic, San Diego, CAGoogle Scholar
  5. 5.
    Hobza P, Sponer J (2002) Toward true DNA base-stacking energies: MP2, CCSD(T), and complete basis set calculations. J Am Chem Soc 124(39):11802–11808CrossRefGoogle Scholar
  6. 6.
    Pérez A, Šponer J, Jurecka P, Hobza P, Luque FJ, Orozco M (2005) Are the hydrogen bonds of RNA (A⋅ U) stronger than those of DNA (A⋅ T)? A quantum mechanics study. Chem Eur J 11(17):5062–5066CrossRefGoogle Scholar
  7. 7.
    Hobza P, Kabelac M, Sponer J, Mejzlik P, Vondrasek J (1997) Performance of empirical potentials (AMBER, CFF95, CVFF, CHARMM, OPLS, POLTEV), semiempirical quantum chemical methods (AM1, MNDO/M, PM3), and ab initio Hartree–Fock method for interaction of DNA bases: comparison with nonempirical beyond Hartree–Fock results. J Comput Chem 18(9):1136–1150CrossRefGoogle Scholar
  8. 8.
    Orozco M, Luque FJ (2000) Theoretical methods for the description of the solvent effect in biomolecular systems. Chem Rev 100(11):4187–4226CrossRefGoogle Scholar
  9. 9.
    Huey R, Mohr SC (1981) Condensed states of nucleic acids. III. psi(+) and psi(-) conformational transitions of DNA induced by ethanol and salt. Biopolymers 20(12):2533–2552CrossRefGoogle Scholar
  10. 10.
    Pohl FM, Jovin TM (1972) Salt-induced co-operative conformational change of a synthetic DNA: equilibrium and kinetic studies with poly (dG-dC). J Mol Biol 67(3):375–396CrossRefGoogle Scholar
  11. 11.
    Bernues J et al (1990) DNA-sequence and metal-ion specificity of the formation of *H-DNA. Nucleic Acids Res 18(14):4067–4073CrossRefGoogle Scholar
  12. 12.
    Wang Y, Patel DJ (1993) Solution structure of the human telomeric repeat d[AG3(T2AG3)3] G-tetraplex. Structure 1(4):263–282CrossRefGoogle Scholar
  13. 13.
    Williamson JR, Raghuraman MK, Cech TR (1989) Monovalent cation-induced structure of telomeric DNA: the G-quartet model. Cell 59(5):871–880CrossRefGoogle Scholar
  14. 14.
    Turner DH (2000) Structure, properties and functions. In: Bloomfield V, Crothers D, Tinoco I (eds) Structure, properties and functions, in nucleic acids. University Science Books, Sausalito, CA, pp 308–310Google Scholar
  15. 15.
    Miyoshi D, Nakamura K, Tateishi-Karimata H, Ohmichi T, Sugimoto N (2009) Hydration of Watson-Crick base pairs and dehydration of Hoogsteen base pairs inducing structural polymorphism under molecular crowding conditions. J Am Chem Soc 131:3522–3531CrossRefGoogle Scholar
  16. 16.
    Gabelica V et al (2007) Base-dependent electron photodetachment from negatively charged DNA strands upon 260-nm laser irradiation. J Am Chem Soc 129(15):4706–4713CrossRefGoogle Scholar
  17. 17.
    Gabelica V, Rosu F, Witt M, Baykut G, De Pauw E (2005) Fast gas-phase hydrogen/deuterium exchange observed for a DNA G-quadruplex. Rapid Commun Mass Spectrom 19(2):201–208CrossRefGoogle Scholar
  18. 18.
    Gale DC, Smith RD (1995) Characterization of noncovalent complexes formed between minor groove binding molecules and duplex DNA by electrospray ionization-mass spectrometry. J Am Soc Mass Spectrom 6(12):1154CrossRefGoogle Scholar
  19. 19.
    Gidden J, Baker ES, Ferzoco AL, Bowers MT (2005) Structural motifs of DNA complexes in the gas phase. Int J Mass Spectrom 240:183–193CrossRefGoogle Scholar
  20. 20.
    Hofstadler SA, Griffey RH (2001) Analysis of noncovalent complexes of DNA and RNA by mass spectrometry. Chem Rev 101(2):377–390CrossRefGoogle Scholar
  21. 21.
    Reyzer ML et al (2001) Evaluation of complexation of metal-mediated DNA-binding drugs to oligonucleotides via electrospray ionization mass spectrometry. Nucleic Acids Res 29(21):E103-3CrossRefGoogle Scholar
  22. 22.
    Rosu F, De Pauw E, Gabelica V (2008) Electrospray mass spectrometry to study drug-nucleic acids interactions. Biochimie 90(7):1074–1087CrossRefGoogle Scholar
  23. 23.
    Rosu F et al (2002) Triplex and quadruplex DNA structures studied by electrospray mass spectrometry. Rapid Commun Mass Spectrom 16(18):1729–1736CrossRefGoogle Scholar
  24. 24.
    Rosu F et al (2010) Tetramolecular G-quadruplex formation pathways studied by electrospray mass spectrometry. Nucleic Acids Res 38(15):5217–5225CrossRefGoogle Scholar
  25. 25.
    Rosu F et al (2007) Ligand binding mode to duplex and triplex DNA assessed by combining electrospray tandem mass spectrometry and molecular modeling. J Am Soc Mass Spectrom 18(6):1052–1062CrossRefGoogle Scholar
  26. 26.
    Schnier PD et al (1998) Activation energies for dissociation of double strand oligonucleotide anions: evidence for Watson-Crick base pairing in vacuo. J Am Chem Soc 120(37):9605–9613CrossRefGoogle Scholar
  27. 27.
    Wan C et al (2008) Studies of the intermolecular DNA triplexes of C + .GC and T.AT triplets by electrospray ionization Fourier-transform ion cyclotron resonance mass spectrometry. J Mass Spectrom 43(2):164–172CrossRefGoogle Scholar
  28. 28.
    Wan KX, Gross ML, Shibue T (2000) Gas-phase stability of double-stranded oligodeoxynucleotides and their noncovalent complexes with DNA-binding drugs as revealed by collisional activation in an ion trap. J Am Soc Mass Spectrom 11(5):450–457CrossRefGoogle Scholar
  29. 29.
    Gabelica V, De Pauw E, Rosu F (1999) Interaction between antitumor drugs and a double-stranded oligonucleotide studied by electrospray ionization mass spectrometry. J Mass Spectrom 34(12):1328–1337CrossRefGoogle Scholar
  30. 30.
    Vairamani M, Gross ML (2003) G-quadruplex formation of thrombin-binding aptamer detected by electrospray ionization mass spectrometry. J Am Chem Soc 125(1):42–43CrossRefGoogle Scholar
  31. 31.
    Wyttenbach T, Bleiholder C, Bowers MT (2013) Factors contributing to the collision cross section of polyatomic ions in the kilodalton to gigadalton range: application to ion mobility measurements. Anal Chem 85:2191–2199CrossRefGoogle Scholar
  32. 32.
    Meyer T, de la Cruz X, Orozco M (2009) An atomistic view to the gas phase proteome. Structure 17(1):88–95CrossRefGoogle Scholar
  33. 33.
    Meyer T, Gabelica V, Grubmüller H, Orozco M (2012) Proteins in the gas phase. WIRES Comput Mol Sci
  34. 34.
    Neutze R, Huldt G, Hajdu J, van der Spoel D (2004) Potential impact of an X-ray free electron laser on structural biology. Radiat Phys Chem 71:905–916CrossRefGoogle Scholar
  35. 35.
    López AT, T, Vilaseca M, Giralt E (2013) New J Chem 37: 1283–1289Google Scholar
  36. 36.
    De la Mora F (2000) J Anal Chim Acta (406):93–104Google Scholar
  37. 37.
    Rayleigh L (1882) Philos Mag: 184–186Google Scholar
  38. 38.
    Fenn JB (1993) Ion formation from charged droplets: roles of geometry, energy, and time. J Am Soc Mass Spectrom 4:524–535CrossRefGoogle Scholar
  39. 39.
    Hautreux M, Hue N, Du Fou de Kerdaniel A, Zahir A, Malec V, Laprévote O (2004) Under non‐denaturing solvent conditions, the mean charge state of a multiply charged protein ion formed by electrospray is linearly correlated with the macromolecular surface. Int J Mass Spectrom 231:131–137CrossRefGoogle Scholar
  40. 40.
    Felitsyn N, Kitova EN, Klassen JS (2002) Thermal dissociation of the protein homodimer ecotin in the gas phase. J Am Soc Mass Spectrom 13(12):1432–1442CrossRefGoogle Scholar
  41. 41.
    Arcella A et al (2012) Structure of triplex DNA in the gas phase. J Am Chem Soc 134(15):6596–6606CrossRefGoogle Scholar
  42. 42.
    Rueda M et al (2003) The structure and dynamics of DNA in the gas phase. J Am Chem Soc 125(26):8007–8014CrossRefGoogle Scholar
  43. 43.
    Rueda M, Luque FJ, Orozco M (2005) Nature of minor-groove binders-DNA complexes in the gas phase. J Am Chem Soc 127(33):11690–11698CrossRefGoogle Scholar
  44. 44.
    McDaniel EW, Mason EA (1988) Transport properties of ions in gases. Wiley, New York, NYGoogle Scholar
  45. 45.
    Wang B, Valentine S, Plasencia M, Raghuraman S, Zhang X (2010) Artificial neural networks for the prediction of peptide drift time in ion mobility mass spectrometry. BMC Bioinforma 11:182CrossRefGoogle Scholar
  46. 46.
    Rueda M, Luque FJ, Orozco M (2006) G-quadruplexes can maintain their structure in the gas phase. J Am Chem Soc 128(11):3608–3619CrossRefGoogle Scholar
  47. 47.
    Madsen JA, Brodbelt JS (2010) Asymmetric charge partitioning upon dissociation of DNA duplexes. J Am Soc Mass Spectrom 21:1144–1150CrossRefGoogle Scholar
  48. 48.
    Cleland WW, Kreevoy MM (1994) Low-barrier hydrogen bonds and enzymic catalysis. Science 264(5167):1887–1890CrossRefGoogle Scholar
  49. 49.
    Rezác J, Hobza P (2013) Describing noncovalent interactions beyond the common approximations: how accurate is then “gold stgandard”, CCSD(T), at the Complete basis set limit. J Chem Theory Comput 9:2151–2155CrossRefGoogle Scholar
  50. 50.
    Orozco M, Cubero E, Barril X, Colominas C, Luque FJ (1999) Nucleic acid bases in solution. In: Leszczynski J (ed) Computational molecular biology, Theoretical computational chemistry. Elsevier Science, Amsterdam, pp 119–166Google Scholar
  51. 51.
    Colominas C, Teixidó J, Cemelí JM, Luque FJ, Orozco M (1998) J Phys Chem B 102:2269–2276CrossRefGoogle Scholar
  52. 52.
    Hernández B, Luque FJ, Orozco M (1996) Tautomerism of xanthine oxidase subtrates hypoxathine and allopurinol. J Org Chem 61:5964–5971CrossRefGoogle Scholar
  53. 53.
    Colominas C, Luque FJ, Orozco M (1996) Tautomerism and protonation of guanine and cytosine. Implications in the formation of triplex DNA. J Am Chem Soc 118:6811–6821CrossRefGoogle Scholar
  54. 54.
    Blas JR, Luque FJ, Orozco M (2004) Unique tautomeric properties of isoguanine. J Am Chem Soc 126:154–164CrossRefGoogle Scholar
  55. 55.
    Orozco M, Canela EI, Mallol J, Lluis C, Franco R (1990) Ab initio study of the protonation and the tautomerism of the 7-aminopyrazolopyrimidine molecule. J Org Chem 55:753–756CrossRefGoogle Scholar
  56. 56.
    Hoaglund CS, Liu Y, Ellington AD, Pagel M, Clemmer DE (1997) Gas-phase DNA: oligothymidine ion conformers. J Am Chem Soc 119:9051–9052CrossRefGoogle Scholar
  57. 57.
    Gidden J, Bowers MT (2002) Gas-phase conformational and energetic properties of deprotonated dinucleotides. Eur Phys J 20:409–419Google Scholar
  58. 58.
    Gidden J et al (2004) Duplex formation and the onset of helicity in poly d(CG)n oligonucleotides in a solvent-free environment. J Am Chem Soc 126(46):15132–15140CrossRefGoogle Scholar
  59. 59.
    Allemand JF et al (1998) Stretched and overwound DNA forms a Pauling-like structure with exposed bases. Proc Natl Acad Sci U S A 95(24):14152–14157CrossRefGoogle Scholar
  60. 60.
    Kosikov MK, Gorin AA, Zhurkin VB, Olson WK (1999) DNA stretching and compression: large-scale simulations of double helical structures. J Mol Biol 289:1301CrossRefGoogle Scholar
  61. 61.
    Laughlan G et al (1994) The high-resolution crystal structure of a parallel-stranded guanine tetraplex. Science 265(5171):520–524CrossRefGoogle Scholar
  62. 62.
    Parkinson GN, Lee MP, Neidle S (2002) Crystal structure of parallel quadruplexes from human telomeric DNA. Nature 417(6891):876–880CrossRefGoogle Scholar
  63. 63.
    Phillips K et al (1997) The crystal structure of a parallel-stranded guanine tetraplex at 0.95 A resolution. J Mol Biol 273(1):171–182CrossRefGoogle Scholar
  64. 64.
    Sen D, Gilbert W (1988) Formation of parallel four-stranded complexes by guanine-rich motifs in DNA and its implications for meiosis. Nature 334(6180):364–366CrossRefGoogle Scholar
  65. 65.
    Gabelica V et al (2008) Infrared signature of DNA G-quadruplexes in the gas phase. J Am Chem Soc 130(6):1810–1811CrossRefGoogle Scholar
  66. 66.
    Rosu F et al (2012) UV spectroscopy of DNA duplex and quadruplex structures in the gas phase. J Phys Chem A 116(22):5383–5391CrossRefGoogle Scholar
  67. 67.
    Balthasart F, Plavec J, Gabelica V (2013) Ammonium ion binding to DNA G-quadruplexes: do electrospray mass spectra faithfully reflect the solution-phase species? J Am Soc Mass Spectrom 24(1):1–8CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Annalisa Arcella
    • 1
    • 2
  • Guillem Portella
    • 1
    • 2
  • Modesto Orozco
    • 1
    • 2
    • 3
    Email author
  1. 1.Institute for Research in Biomedicine (IRB Barcelona)BarcelonaSpain
  2. 2.Joint Research Program in Computational BiologyInstitute for Research in Biomedicine and Barcelona Supercomputing CenterBarcelonaSpain
  3. 3.Department of Biochemistry and Molecular BiologyUniversity of BarcelonaBarcelonaSpain

Personalised recommendations