Applied Biological Chemistry

, Volume 61, Issue 2, pp 209–226 | Cite as

An in-depth study on noncovalent stacking interactions between DNA bases and aromatic drug fragments using DFT method and AIM analysis: conformers, binding energies, and charge transfer

  • Hossein Azizi Toupkanloo
  • Zoha Rahmani


This work is aimed at providing physical insights about the ππ stacking interactions of some popular drug fragments (DF) including indole (I), benzothiophene (Bt), benzofuran (Bf) and guanine (G), adenine (A), A-thymine (AT), G-cytosine (GC) base pairs using density functional theory (DFT), the atoms in molecule (AIM) theory, and natural bond orbital (NBO) analysis. Several stable conformers of present molecules and complexes were optimized at the M062X/6-311++G(d,p) level of theory. The result shows that the IG1 (see the notation below) and IA6 have maximum interaction energy in all of the two G-based and A-based conformers; and order of the adsorption strength is IG1 > BtG6 > BfG1 for G-based complexes and IA6 > BtA6 > BfG6 for A-based complexes. For the base pair–drug fragment complexes, the order of interaction energy was found according to IAT4 > BtAT3 > BfAT4 and IGC3 > BtGC2 > BfGC2, for AT and GC base pairs, respectively. Furthermore, our results show that stacking interaction leads to an increase and decrease in hydrogen bond length that involved in the nucleic base–drug fragment interactions. DFT-calculated interaction energies for all present conformers were found to be in a good agreement with the bond critical points data from AIM analysis. In contrast, no reasonable linear correlation was observed between NBO analysis and stability of the all studied conformers. Finally, in order to verify the DFT and AIM results, docking calculations were performed using AutoDock software. According to the binding energy of drug–DNA from AutoDock calculations, the D2-Bt and D1-Bf are the most and the least stable structures, respectively.


AutoDock Binding energy Drug fragment Interaction energy ππ stacking 



Authors are very indebted to Research Committee of the University of Sistan and Baluchestan due to its authorities for financial support during the tenure of which work was completed.

Supplementary material

13765_2018_348_MOESM1_ESM.docx (258 kb)
Supplementary material 1 (DOCX 258 kb)
13765_2018_348_MOESM2_ESM.docx (34 kb)
Supplementary material 2 (DOCX 34 kb)


  1. 1.
    Bradley DDC (2014) Organic electronics and photonics: concluding remarks. Faraday Discuss 174:429–438CrossRefGoogle Scholar
  2. 2.
    Kool ET (2001) Hydrogen bonding, base stacking, and steric effects in DNA replication. Annu Rev Biophys Biomol Struct 30:1–22CrossRefGoogle Scholar
  3. 3.
    Muraki M (2002) The importance of CH/π interactions to the function of carbohydrate binding proteins. Protein Peptide Lett 9:195–209CrossRefGoogle Scholar
  4. 4.
    Burley SK, Petsko GA (1985) Aromatic–aromatic interaction: a mechanism of protein structure stabilization. Science 229:23–28CrossRefGoogle Scholar
  5. 5.
    Meyer EA, Castellano RK, Diederich F (2003) Interactions with aromatic rings in chemical and biological recognition. Angew Chem Int Ed 42:1210–1250CrossRefGoogle Scholar
  6. 6.
    Kumar S, Mukherjee A, Das A (2012) Structure of indole···imidazole heterodimer in a supersonic jet: a gas phase study on the interaction between the aromatic side chains of tryptophan and histidine residues in proteins. J Phys Chem A 116:11573–11580CrossRefGoogle Scholar
  7. 7.
    Hunter CA, Singh J, Thornton JM (1991) ππ interactions: the geometry and energetics of phenylalanine-phenylalanine interactions in proteins. J Mol Biol 218:837–846CrossRefGoogle Scholar
  8. 8.
    Rutledge LR, Campbell-Verduyn LS, Hunter KC, Wetmore SD (2006) Characterization of nucleobase–amino acid stacking interactions utilized by a DNA repair enzyme. J Phys Chem B 110:19652–19663CrossRefGoogle Scholar
  9. 9.
    Rutledge LR, Campbell-Verduyn LS, Wetmore SD (2007) Characterization of the stacking interactions between DNA or RNA nucleobases and the aromatic amino acids. Chem Phys Lett 444:167–175CrossRefGoogle Scholar
  10. 10.
    Huber RG, Margreiter MA, Fuchs JE, von Grafenstein S, Tautermann CS, Liedl KR, Fox T (2014) Heteroaromatic π-stacking energy landscapes. J Chem Inf Model 54:1371–1379CrossRefGoogle Scholar
  11. 11.
    Salonen LM, Ellermann M, Diederich F (2011) Aromatic rings in chemical and biological recognition: energetics and structures. Angew Chem Int Ed 50:4808–4842CrossRefGoogle Scholar
  12. 12.
    Neidle, S (2008) Principles of nucleic acid structure. Elsevier, New York (Chapter 6)Google Scholar
  13. 13.
    Řeha D, Kabeláč M, Ryjáček F, Šponer J, Šponer JE, Elstner M, Suhai S, Hobza P (2002) Intercalators. 1. Nature of stacking interactions between intercalators (ethidium, daunomycin, ellipticine, and 4‘,6-diaminide-2-phenylindole) and DNA base pairs. ab initio quantum chemical, density functional theory, and empirical potential study. J Am Chem Soc 124:3366–3376CrossRefGoogle Scholar
  14. 14.
    Brana MF, Cacho M, Gradillas A, Pascual-Teresa B, Ramos A (2001) Intercalators as anticancer drugs. Curr Pharm Des 7:1745–1780CrossRefGoogle Scholar
  15. 15.
    Brovarets OHO, Yurenko YP, Hovorun DM (2015) The significant role of the intermolecular CH···O/N hydrogen bonds in governing the biologically important pairs of the DNA and RNA modified bases: a comprehensive theoretical investigation. J Biomol Struct Dyn 33:1624–1652CrossRefGoogle Scholar
  16. 16.
    Calladine CR, Drew HR (1992) Understanding DNA. Academic Press, LondonGoogle Scholar
  17. 17.
    Saenger W (1984) Principles of nucleic acid structure. Springer, New York, pp 132–140CrossRefGoogle Scholar
  18. 18.
    Wakelin LPG (1986) Polyfunctional DNA intercalating agents. Med Res Rev 6:275–340CrossRefGoogle Scholar
  19. 19.
    Desiraju GR, Gavezzotti A (1989) From molecular to crystal structure; polynuclear aromatic hydrocarbons. J Chem Soc Chem Commun 10:621–623CrossRefGoogle Scholar
  20. 20.
    Burley SK, Petsko GA (1988) Weakly polar interactions in proteins. Adv Protein Chem 39:125–189CrossRefGoogle Scholar
  21. 21.
    Suzuki M, Amano N, Kakinuma J, Tateno M (1997) Use of a 3D structure data base for understanding sequence-dependent conformational aspects of DNA1. J Mol Biol 274:421–435CrossRefGoogle Scholar
  22. 22.
    Burkard ME, Kierzek R, Turner DH (1999) Thermodynamics of unpaired terminal nucleotides on short RNA helixes correlates with stacking at helix termini in larger RNAs1. J Mol Biol 290:967–982CrossRefGoogle Scholar
  23. 23.
    Wu P, Nordlund TM, Gildea B, McLaughlin LW (1990) Base stacking and unstacking as determined from a DNA decamer containing a fluorescent base. Biochemistry 29:6508–6514CrossRefGoogle Scholar
  24. 24.
    Swart M, van der Wijst T, Fonseca Guerra C, Bickelhaupt FM (2007) ππ stacking tackled with density functional theory. J Mol Model 13:1245–1257CrossRefGoogle Scholar
  25. 25.
    Gu J, Wang J, Leszczynski J, Xie Y, Schaefer Iii HF (2008) To stack or not to stack: performance of a new density functional for the uracil and thymine dimers. Chem Phys Lett 459:164–166CrossRefGoogle Scholar
  26. 26.
    Cysewski P, Czyżnikowska-Balcerak Ż (2005) The MP2 quantum chemistry study on the local minima of guanine stacked with all four nucleic acid bases in conformations corresponding to mean B-DNA. J Mol Struct (Thoechem) 757:29–36CrossRefGoogle Scholar
  27. 27.
    Cysewski P, Czyżnikowska-Balcerak Ż (2007) A post-SCF quantum chemistry study on local minima of 8-oxo-guanine stacked with all four nucleic acid bases in B-DNA conformations. J Heterocycl Chem 44:765–773CrossRefGoogle Scholar
  28. 28.
    Sharma V, Kumar P, Pathak D (2010) Biological importance of the indole nucleus in recent years: a comprehensive review. J Heterocycl Chem 47:491–502Google Scholar
  29. 29.
    Vicente R (2011) Recent advances in indole syntheses: new routes for a classic target. Org Biomol Chem 9:6469–6480CrossRefGoogle Scholar
  30. 30.
    Khanam H, Uzzaman S (2015) Bioactive Benzofuran derivatives: a review. Eur J Med Chem 97:483–504CrossRefGoogle Scholar
  31. 31.
    Ferreira AP, da Silva JLF, Duarte MT, da Piedade MFM, Robalo MP, Harjivan SG, Marzano C, Gandin V, Marques MM (2009) Synthesis and characterization of new organometallic benzo[b]thiophene derivatives with potential antitumor properties. Organometallics 28:5412–5423CrossRefGoogle Scholar
  32. 32.
    Queiroz M-JRP, Ferreira ICFR, Gaetano YD, Kirsch G, Calhelha RC, Estevinho LM (2006) Synthesis and antimicrobial activity studies of ortho-chlorodiarylamines and heteroaromatic tetracyclic systems in the benzo[b]thiophene series. Bioorg Med Chem 14:6827–6831CrossRefGoogle Scholar
  33. 33.
    Akher FB, Ebrahimi A, Mostafavi N (2017) Characterization of p-stacking interactions between aromatic amino acids and quercetagetin. J Mol Struct 1128:13–20CrossRefGoogle Scholar
  34. 34.
    Schneider H-J (2009) Binding mechanisms in supramolecular complexes. Angew Chem Int Ed 48:3924–3977CrossRefGoogle Scholar
  35. 35.
    Dougherty DA (1996) Cation-pi interactions in chemistry and biology: a new view of benzene, Phe, Tyr and Trp. Science 271:163–168CrossRefGoogle Scholar
  36. 36.
    Harder M, Kuhn B, Diederich F (2013) Efficient stacking on protein amide fragments. ChemMedChem 8:397–404CrossRefGoogle Scholar
  37. 37.
    Wallnoefer HG, Fox T, Liedl KR, Tautermann CS (2010) Dispersion dominated halogen-[small pi] interactions: energies and locations of minima. Phys Chem Chem Phys 12:14941–14949CrossRefGoogle Scholar
  38. 38.
    Janiak C (2000) A critical account on [small pi]-[small pi] stacking in metal complexes with aromatic nitrogen-containing ligands. J Chem Soc, Dalton Trans 21:3885–3896CrossRefGoogle Scholar
  39. 39.
    Snyder RD, Holt PA, Maguire JM, Trent JO (2013) Prediction of noncovalent Drug/DNA interaction using computational docking models: studies with over 1350 launched drugs. Environ Mol Mutagen 54:668–681CrossRefGoogle Scholar
  40. 40.
    Trucks GW, Frisch MJ, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Petersson GA, Nakatsuji H, Li X, Caricato M, Marenich A, Bloino J, Janesko BG, Gomperts R, Mennucci B, Hratchian HP, Ortiz JV, Izmaylov AF, Sonnenberg JL, Williams-Young D, Ding F, Lipparini F, Egidi F, Goings J, Peng B, Petrone A, Henderson T, Ranasinghe D, Zakrzewski VG, Gao J, Rega N, Zheng G, Liang W, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Throssell K, Montgomery JA Jr, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Keith T, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Millam JM, Klene M, Adamo C, Cammi R, Ochterski JW, Martin RL, Morokuma K, Farkas O, Foresman JB, Fox DJ (2009) Gaussian 09 CitationGoogle Scholar
  41. 41.
    Boys SF, Bernardi F (1970) The calculation of small molecular interactions by the differences of separate total energies. Some procedures with reduced errors. Mol Phys 19:553–566CrossRefGoogle Scholar
  42. 42.
    Zhao Y, Truhlar DG (2008) The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06 functionals and 12 other functionals. Theoret Chem Acc 119:525CrossRefGoogle Scholar
  43. 43.
    Wheeler SE, Bloom JWG (2014) Toward a more complete understanding of noncovalent interactions involving aromatic rings. J Phys Chem A 118:6133–6147CrossRefGoogle Scholar
  44. 44.
    Riley KE, Hobza P (2011) Noncovalent interactions in biochemistry. Wiley Interdiscip Rev Comput Mol Sci 1:3–17CrossRefGoogle Scholar
  45. 45.
    Reed AE, Curtiss LA, Weinhold F (1988) Intermolecular interactions from a natural bond orbital, donor-acceptor viewpoint. Chem Rev 88:899–926CrossRefGoogle Scholar
  46. 46.
    Bader RFW (1990) Atoms in molecules: a quantum theory. Clarendon Press, OxfordGoogle Scholar
  47. 47.
    Biegler-Konig F, Schonbohm J, Bayles D (2001) AIM2000. J Comput Chem 22:545–559CrossRefGoogle Scholar
  48. 48.
    Breneman Curt M, Wiberg Kenneth B (1990) Determining atom-centered monopoles from molecular electrostatic potentials. The need for high sampling density in formamide conformational analysis. J Comput Chem 11:361–373CrossRefGoogle Scholar
  49. 49.
    Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791CrossRefGoogle Scholar
  50. 50.

Copyright information

© The Korean Society for Applied Biological Chemistry 2018

Authors and Affiliations

  1. 1.Department of Physics and Chemistry, Faculty of ScienceUniversity of NeyshaburNeyshaburIran
  2. 2.Computational Quantum Chemistry Laboratory, Department of ChemistryUniversity of Sistan and BaluchestanZahedanIran

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