Skip to main content
SpringerLink
Log in

Theoretical investigation on hydrogen bond interaction of diketo/keto-enol form uracil and thymine tautomers with intercalators

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

Abstract

The interaction of diketo and keto-enol form of thymine and uracil tautomers with acridine (Acr), phenazine (Phen), benzo[c]cinnoline (Ben), 1,10-phenanthroline (1,10-Phe), and 4,7-phenenthroline (4,7-Phe) intercalating drug molecules was studied using density functional theory at B3LYP/6–311++G** and M05-2×/6–311++G** levels of theory. From the interaction energy, it is found that keto-enol form tautomers have stronger interaction with intercalators than diketone form tautomers. On complex formation of thymine and uracil tautomers with benzo[c]cinnoline the drug molecules have high interaction energy values of −20.14 (BenT3) and −20.55 (BenU3) kcal mol-1, while phenazine has the least interaction energy values of −6.52 (PhenT2) and −6.67 (PhenU2) kcal mol-1. The closed shell intermolecular type interaction between the molecules with minimum elliptical value of 0.018 and 0.019 a.u at both levels of theory has been found from topological analysis. The benzo[c]cinnoline drug molecule with thymine and uracil tautomers has short range intermolecular N-H…N, C-H…O, and O-H...N hydrogen bonds (H-bonds) resulting in higher stability than other drug molecules. The proper hydrogen bonds N-H..N and O-H..N have the frequency shifted toward the lower side (red shifted) with the elongation in their bond length while the improper hydrogen bond C-H...O has the frequency shifted toward the higher side (blue shifted) of the spectral region with the contraction in their bond length. Further, the charge transfer between proton acceptor and donor along with stability of the bond is studied using natural bond orbital (NBO) analysis.

Graphical abstract

Hydrogen bond interaction of diketo/keto-enol form uracil and thymine tautomers with intercalators

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Orozco M, López JM, Colomines C, Alhambra C, Busquets MA, Luque FJ (1995). J Am Chem Soc 117:1378–1386

    Article  CAS  Google Scholar 

  2. Sayle RA (2010) So you think you understand tautomerism? J Comput Aided Mol Des 24:485–496

    Article  CAS  Google Scholar 

  3. Fan JC, Shang ZC, Liang J, et al. (2010) Systematic theoretical investigations on the tautomers of thymine in gas phase and solution. J Mol Struct THEOCHEM 939:106–111

    Article  CAS  Google Scholar 

  4. Rejnek J, Hanus M, Kabeláč M, Ryjáček F, Hobza P (2005) Correlated ab initio study of nucleic acid bases and their tautomers in the gas phase, in a microhydrated environment and in aqueous solution part 4 uracil and thymine. Phys Chem Chem Phys 7:2006–2017

  5. Bodor N, Dewar MJS, Harget AJ (1970) Ground state of conjugated molecules XIX : tautomerism of heteroaromatic, hydroxy and amino derivatives and nucleotide bases. J Am Chem Soc 3217:2929–2936

    Article  Google Scholar 

  6. Buda A, Sygula A (1983) MNDO study of the tautomers of nucleic bases part I. Uracil, thymine and cytosine. J Mol Struct THEOCHEM 92:255–265

  7. Scanlan MJ, Hillier IH (1984) An ab Initio Study of the tautomerism of uracil thymine 5-fluorouracil and cytosine. J Am Chem Soc 106:3737–3745

    Article  CAS  Google Scholar 

  8. Norinder U (1987) A theoretical reinvestigation of the nucleic bases adenine, guanine, cytosine, thymine and uracil using AM1. J Mol Struct THEOCHEM 151:259–269

    Article  Google Scholar 

  9. Lest A, Adamowicz L (1989) Oxo-hydroxy tautomerism of uracil and 5-fluorouracll. J Phys Chem 85721:7078–7081

  10. Orozco M, Hernandez B, Luque FJ (1998) Tautomerism of 1-methyl derivatives of uracil, thymine, and 5-bromouracil. Is tautomerism the basis for the mutagenicity of 5-bromouridine? J Phys Chem B 5647:5228–5233

  11. Beak P (1977) Energies and alkylations of tautomeric heterocyclic compounds: old problems-new answers. Acc Chem Res 10:186–192

    Article  CAS  Google Scholar 

  12. Rostkowska H, Szczepaniak K, Nowak MJ, Leszczynski J, Kubulat K, Person WB (1990) Tautomerism and infrared spectra of thiouracils. Matrix isolation and ab initio studies. J Am Chem Soc 112:2147–2160

    Article  CAS  Google Scholar 

  13. Person WB, Szczepaniak K, Szczesniak M, Kwiatkowski JS, Hernandez L, Czerminski R (1989) Tautomerism of nucleic acid bases and the effect of molecular interactions on tautomeric equilibria. J Mol Struct 194:239–258

  14. Zhang R, Ceulemans A, Nguyen MT (2005) A theoretical study of uracil and its tautomers in their lowest-lying triplet state. Mol Phys 103:983–994

  15. Civcir PÜ (2000) A theoretical study of tautomerism of cytosine, thymine, uracil and their 1-methyl analogues in the gas and aqueous phases using AM1 and PM3. J Mol Struct THEOCHEM 532:157–169

    Article  CAS  Google Scholar 

  16. Deepa P, Kolandaivel P (2012) Studies on Tautomeric forms of Guanine-Cytosine base pairs of nucleic acids and their interactions with water molecules. J Biomol Struct Dyn 25:733–746

    Article  Google Scholar 

  17. Watson JD, Crick FHC (1969) Molecular structure of nucleic acids: a structure for deoxyribose nucleic acid (Reprinted from Nature, April 25, 1953). Nature 224:470–471

  18. Ferguson LR, Denny WA (2007) Genotoxicity of non-covalent interactions: DNA intercalators. Mutat Res Fundam Mol Mech Mutagen 623:14–23

    Article  CAS  Google Scholar 

  19. Hochstrasser RM (1962) Absorption spectrum of phenazine single crystals at 77° and 4.2°K in the Region of the n→π Transition. J Chem Phys doi:10.1063/1.1701271

  20. Kallir AJ, Suter GW, Wild UP (1985) Multiple phosphorescence of phenazine in ethanol at 77 K. J Phys Chem 89:1996–1999

    Article  CAS  Google Scholar 

  21. Aaron JJ, Maafi M, Párkányi C, Boniface C (1995) Quantitative treatment of the solvent effects on the electronic absorption and fluorescence spectra of acridines and phenazines. The ground and first excited singlet-state dipole moments. Spectrochim Acta A Mol Spectrosc 51:603–615

    Article  Google Scholar 

  22. Hirata Y, Tanaka I (1976) Intersystem crossing to the lowest triplet state of phenazine following singlet excitation with a picosecond pulse. Chem Phys Lett 43:568–570

    Article  CAS  Google Scholar 

  23. Grabowska A (1967) Triplet states of six-membered N-herterocycles spin-orbital coupling in diazines. Chem Phys Lett 1:113–116

  24. Del Barrio JI, Rebato JR, G. -Tablas FM (1989) Basicity of phenazine in the first triplet state. J Phys Chem 93:6836–6837

    Article  Google Scholar 

  25. Denny WA, Turner PM, Atwell GJ, et al. (1990) Structure-activity relationships for the mutagenic activity of tricyclic intercalating agents in Salmonella typhimurium. Mutat Res Fundam Mol Mech Mutagen 232:233–241

    Article  CAS  Google Scholar 

  26. Vives M, Gargallo R, Tauler R (2000) Multivariate extension of the continuous variation and mole-ratio methods for the study of the interaction of intercalators with polynucleotides. Anal Chim Acta 424:105–114

    Article  CAS  Google Scholar 

  27. Pilia L, Pizzotti M, Tessore F, Robertson N (2015) Tuning the LUMO energy of 1,10-phenanthroline in α-diimine–dithiolate Ni(II) complex and enhancement of nonlinear optical properties. Inorg Chim Acta 430:114–119

    Article  CAS  Google Scholar 

  28. Choudhury SD, Basu S (2005) Interaction of phenazine with water and DNA bases. Spectrochim Acta A Mol Biomol Spectrosc 62:736–739

    Article  Google Scholar 

  29. Sponer J, Jurecka P, Hobza P (2004) Accurate interaction energies of hydrogen-bonded nucleic acid base pairs. J Am Chem Soc 126:10142–10151

    Article  CAS  Google Scholar 

  30. Becke AD (1993) Density-functional thermochemistry. III. The role of exact exchange. J Chem Phys 98:5648

    Article  CAS  Google Scholar 

  31. Lee C, Yang W, Parr RG (1988) Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys Rev B 37:785–789

    Article  CAS  Google Scholar 

  32. Li YM, Zhou XM, Tang K, Qin M, Zhou ZY (2010) DFT studies on Hydrogen bonded complexes of thymine with formamide. Indian J Chem Sect A Inorg Phys Theor Anal Chem 49:145–150

    Google Scholar 

  33. Hall RJ, Hillier IH, Vincent MA (2000) Which density functional should be used to model hydration? Chem Phys Lett 320:139–143

    Article  CAS  Google Scholar 

  34. Zhao Y, Schultz NE, Truhlar DG (2006) Design of density functionals by combining the method of constraint satisfaction with parametrization for thermochemistry, thermochemical kinetics, and noncovalent interactions. J Chem Theory Comput 2:364–382

    Article  Google Scholar 

  35. Zhao Y, Truhlar DG (2007) Density functionals for noncovalent interaction energies of biological importance density functionals for noncovalent interaction energies of biological importance. J Chem Theory Comput 3:289–300

  36. Boys S, Bernardi F (1970) The calculation of small molecular interactions by the differences of separate total energies. Some procedures with reduced errors. Mol Phys 19:553–566

    Article  CAS  Google Scholar 

  37. Popelier PLA, Bader W (1992) The existence of an intramolecular C-H-O hydroen bond in creatine and carbamoyl sarcosine. Chem Phys Lett 189:542–548

  38. Cheeseman JR, Carroll MT, Bader RFW (1988) Themechanics of hydrogen bond formation in conjugated systems. Chem Phys Lett 143:450–458

  39. MORPHY98 (1998) A program written by P.L.A. Popelier with a contribution from R.G.A Bone. UMIST, Manchester

  40. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery Jr JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09, revision A.1. Gaussian Inc, Wallingford

  41. Rozas I (2007) On the nature of hydrogen bonds: an overview on computational studies and a word about patterns. Phys Chem Chem Phys 9:2782–2790

    Article  CAS  Google Scholar 

  42. Dolgounitcheva O, Zakrzewski VG, Ortiz JV (1997) Ionization energies of acridine, phenazine, and diazaphenanthrenes. J Phys Chem A 101:8554–8564

  43. Cubero E, Orozco M, Hobza P, Luque FJ (1999) Hydrogen bond versus anti-hydrogen bond: a comparative analysis based on the electron density topology. J Phys Chem A 103:6394–6401

  44. Van der Veken BJ, Herrebout WA, Szostak R et al. (2001) The nature of improper, blue-shifting hydrogen bonding verified experimentally. J Am Chem Soc 123:12290–12293

    Article  Google Scholar 

  45. Hobza P, Havlas Z (2000) Blue-shifting hydrogen bonds. Chem Rev 100:4253–4264

  46. Bent HA (1960) distribution of molecules and atomic s character in its chemical implications. J Chem Educ 37:616–624

    Article  CAS  Google Scholar 

  47. Shirley WA, Hoffmann R, Mastryukov VS (1995) Anapproach to understanding bond length/bond angle relationships. J Phys Chem 99:4025–4033

  48. Burns LA, Vázquez-Mayagoitia Á, Sumpter BG, David Sherrill C (2011) Density-functional approaches to noncovalent interactions: a comparison of dispersion corrections (DFT-D), exchange-hole dipole moment (XDM) theory, and specialized functionals. J Chem Phys 134:084107

  49. Singh SK, Kumar S, Das A (2014) Competition between n-πAr* and conventional hydrogen bonding (N–H…N) interactions: an ab initio study of the complexes of 7-azaindole and fluorosubstituted pyridines. Phys Chem Chem Phys 16:8819–8827

  50. Shankar R, Radhika R, Thangamani D, Senthil Kumar L, Kolandaivel P (2014) Theoretical studies on interaction of anticancer drugs (dacarbazine, procarbazine and triethylenemelamine) with normal (AT and GC) and mismatch (GG, CC, AA and TT) base pairs. Mol Simul 7022:1–20

    Google Scholar 

  51. Popelier PLA (2000) Atoms in molecules: an introduction. Pearson, London

  52. Bader RFW (1991) A quantum theory of molecular structure and its applications. Chem Rev 91:893–928

    Article  CAS  Google Scholar 

  53. Paul BK, Mahanta S, Singh RB, Guchhait N (2010) A DFT-based theoretical study on the photophysics of 4-hydroxyacridine: single-water-mediated excited state proton transfer. J Phys Chem A 114:2618–2627

  54. Popelier PLA (1998) Characterization of a dihydrogen bond on the basis of the electron density. J Phys Chem A 102:1873–1878

  55. Yogeswari B, Kanakaraju R, Boopathi S, Kolandaivel P (2012) Microsolvation and hydrogen bond interactions in glycine dipeptide: molecular dynamics and density functional theory studies. J Mol Graph Model 35:11–20

  56. Love I (2012) A QTAIM analysis of Cl, O bonds. Comput Theor Chem 985:23–29

    Article  CAS  Google Scholar 

  57. Parthasarathi R, Subramanian V, Sathyamurthy N (2007) Hydrogen bonding in protonated water clusters: an atoms-in-molecules perspective. J Phys Chem A 111:13287–13290

  58. Silva López C, Nieto Faza O, Cossió FP, et al. (2005) Ellipticity: a convenient tool to characterize electrocyclic reactions. Chem Eur J 11:1734–1738

  59. Lu YX, Zou JW, Wang YH, et al. (2007) Ab initio investigation of the complexes between bromobenzene and several electron donors: Some insights into the magnitude and nature of halogen bonding interactions. J Phys Chem A 111:10781–10788

    Article  CAS  Google Scholar 

  60. Arnold WD, Oldfield E (2000) The chemical nature of hydrogen bonding in proteins via NMR: J-couplings, chemical shifts, and AIM theory. J Am Chem Soc 122:12835–12841

    Article  CAS  Google Scholar 

  61. Dunning Jr TH, Cartwright DC, Hunt WJ, et al. (1976) Generalized valence bond calculations on the ground state of nitrogen. J Chem Phys 64:4755

    Article  CAS  Google Scholar 

  62. Niu X, Huang Z, Ma L, et al. (2013) Density functional theory, natural bond orbital and quantum theory of atoms in molecule analyses on the hydrogen bonding interactions in tryptophan-water complexes. J Chem Sci 125:949–958

    Article  CAS  Google Scholar 

  63. Alabugin IV, Manoharan M, Peabody S, Weinhold F (2003) Electronic basis of improper hydrogen bonding: a subtle balance of hyperconjugation and rehybridization. J Am Chem Soc 125:5973–5987

  64. Buemi G, Zuccarello F (2002) Is the intramolecular hydrogen bond energy valuable from internal rotation barriers? J Mol Struct 581:71–85

    Article  CAS  Google Scholar 

  65. Ajayaghosh A (2003) Donor—acceptor type low band gap polymers: polysquaraines and related systems. Chem Soc Rev 32:181–191

  66. Pearson RG (2005) Chemical hardness and density functional theory. J Chem Sci 117:369–377

  67. Li AY, Wang SW (2007) Ab initio investigation of hydrogen bonds between pyridine and HCl, CHCl3. J Mol Struct THEOCHEM 807:191–199

    Article  CAS  Google Scholar 

Download references

Acknowledgments

SV expresses his sincere thanks to the Department of Science and Technology (DST-SERB), Government of India for the financial support in the form of a project.

Author information

Authors and Affiliations

  1. Department of Physics, Bharathiar University, Coimbatore, 641046, India

    V. S. Anithaa, M. Sudha & R. Shankar

  2. Department of Medical Physics, Bharathiar University, Coimbatore, 641046, India

    S. Vijayakumar

Authors
  1. V. S. Anithaa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Vijayakumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Sudha
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Shankar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. Vijayakumar.

Electronic supplementary material

ESM 1

(DOCX 744 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Anithaa, V.S., Vijayakumar, S., Sudha, M. et al. Theoretical investigation on hydrogen bond interaction of diketo/keto-enol form uracil and thymine tautomers with intercalators. J Mol Model 23, 333 (2017). https://doi.org/10.1007/s00894-017-3476-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00894-017-3476-8

Keywords

Search

Navigation