Anion–π interactions in complexes of proteins and halogen-containing amino acids

  • Sunčica Z. Borozan
  • Mario V. Zlatović
  • Srđan Đ. StojanovićEmail author
Original Paper


We analyzed the potential influence of anion–π interactions on the stability of complexes of proteins and halogen-containing non-natural amino acids. Anion–π interactions are distance and orientation dependent and our ab initio calculations showed that their energy can be lower than −8 kcal mol−1, while most of their interaction energies lie in the range from −1 to −4 kcal mol−1. About 20 % of these interactions were found to be repulsive. We have observed that Tyr has the highest occurrence among the aromatic residues involved in anion–π interactions, while His made the least contribution. Furthermore, our study showed that 67 % of total interactions in the dataset are multiple anion–π interactions. Most of the amino acid residues involved in anion–π interactions tend to be buried in the solvent-excluded environment. The majority of the anion–π interacting residues are located in regions with helical secondary structure. Analysis of stabilization centers for these complexes showed that all of the six residues capable of anion–π interactions are important in locating one or more of such centers. We found that anion–π interacting residues are sometimes involved in simultaneous interactions with halogens as well. With all that in mind, we can conclude that the anion–π interactions can show significant influence on molecular organization and on the structural stability of the complexes of proteins and halogen-containing non-natural amino acids. Their influence should not be neglected in supramolecular chemistry and crystal engineering fields as well.


Anion–π interactions Halogen-containing amino acids Proteins Stabilization centers Interaction energy 



This work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grants Nos. 172001, 172055, 173034).

Supplementary material

775_2016_1346_MOESM1_ESM.pdf (928 kb)
Supplementary material 1 (PDF 928 kb)


  1. 1.
    Stojanović SĐ, Medaković VB, Predović G, Beljanski M, Zarić SD (2007) J Biol Inorg Chem 12:1063–1071CrossRefPubMedGoogle Scholar
  2. 2.
    Salonen LM, Ellermann M, Diederich F (2011) Angew Chem Int Ed Engl 50:4808–4842CrossRefPubMedGoogle Scholar
  3. 3.
    Sivasakthi V, Anbarasu A, Ramaiah S (2013) Cell Biochem Biophys 67:853–863CrossRefPubMedGoogle Scholar
  4. 4.
    Wang DX, Wang MX (2013) J Am Chem Soc 135:892–897CrossRefPubMedGoogle Scholar
  5. 5.
    Gamez P (2014) Inorg Chem Front 1:35–43CrossRefGoogle Scholar
  6. 6.
    Liu W, Wang QQ, Wang Y, Huang ZT, Wang DX (2014) RSC Adv 4:9339–9342CrossRefGoogle Scholar
  7. 7.
    Aragay G, Frontera A, Lloveras V, Vidal-Gancedo J, Ballester P (2013) J Am Chem Soc 135:2620–2627CrossRefPubMedGoogle Scholar
  8. 8.
    Chifotides HT, Giles ID, Dunbar KR (2013) J Am Chem Soc 135:3039–3055CrossRefPubMedGoogle Scholar
  9. 9.
    Mohan N, Suresh CH (2014) J Phys Chem A 118:4315–4324CrossRefPubMedGoogle Scholar
  10. 10.
    Robertazzi A, Krull F, Knapp EW, Gamez P (2011) CrystEngComm 13:3293–3300CrossRefGoogle Scholar
  11. 11.
    Mooibroek TJ, Gamez P (2012) CrystEngComm 14:3902–3906CrossRefGoogle Scholar
  12. 12.
    Hafezi N, Holcroft JM, Hartlieb KJ, Dale EJ, Vermeulen NA, Stern CL, Sarjeant AA, Stoddart JF (2015) Angew Chem 127:466–471CrossRefGoogle Scholar
  13. 13.
    Chakravarty S, Sheng ZZ, Iverson B, Moore B (2012) FEBS Lett 586:4180–4185CrossRefPubMedGoogle Scholar
  14. 14.
    Jenkins DD, Harris JB, Howell EE, Hinde RJ, Baudry J (2013) J Comput Chem 34:518–522CrossRefPubMedGoogle Scholar
  15. 15.
    Jones GJ, Robertazzi A, Platts JA (2013) J Phys Chem B 117:3315–3322CrossRefPubMedGoogle Scholar
  16. 16.
    Frontera A, Gamez P, Mascal M, Mooibroek TJ, Reedijk J (2011) Angew Chem Int Ed Engl 50:9564–9583CrossRefPubMedGoogle Scholar
  17. 17.
    Philip V, Harris J, Adams R, Nguyen D, Spiers J, Baudry J, Howell EE, Hinde RJ (2011) Biochemistry 50:2939–2950CrossRefPubMedGoogle Scholar
  18. 18.
    Estarellas C, Frontera A, Quiňonero D, Deyà PM (2011) Chem Asian J 6:2316–2318CrossRefPubMedGoogle Scholar
  19. 19.
    Guha S, Saha S (2010) J Am Chem Soc 132:17674–17677CrossRefPubMedGoogle Scholar
  20. 20.
    Nadella S, Selvakumar PM, Suresh E, Subramanian PS, Albrecht M, Giese M, Fröhlich R (2012) Chem Eur J 18:16784–16792CrossRefPubMedGoogle Scholar
  21. 21.
    Vargas Jentzsch A, Hennig A, Mareda J, Matile S (2013) Acc Chem Res 46:2791–2800Google Scholar
  22. 22.
    Kane Dickson V, Pedi L, Long SB (2014) Nature 516:213–218Google Scholar
  23. 23.
    Campo-Cacharrón A, Cabaleiro-Lago EM, González-Veloso I, Rodríguez-Otero J (2014) J Phys Chem A 118:6112–6124PubMedGoogle Scholar
  24. 24.
    Fang X, Guo MD, Weng LJ, Chen Y, Lin MJ (2015) Dyes Pigm 113:251–256CrossRefGoogle Scholar
  25. 25.
    Gamez P, Mooibroek TJ, Teat SJ, Reedijk J (2007) Acc Chem Res 40:435–444CrossRefPubMedGoogle Scholar
  26. 26.
    Krieger IV, Freundlich JS, Gawandi VB, Roberts JP, Gawandi VB, Sun Q, Owen JL, Fraile MT, Huss SI, Lavandera JL, Ioerger TR, Sacchettini JC (2012) Chem Biol 19:1556–1567CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Bauzá A, Quiňonero D, Deyà PM, Frontera A (2014) Chem Eur J 20:6985–6990CrossRefPubMedGoogle Scholar
  28. 28.
    Chifotides HT, Schottel BL, Dunbar KR (2010) Angew Chem Int Ed Engl 49:7202–7207CrossRefPubMedGoogle Scholar
  29. 29.
    Wang DX, Fa SX, Liu Y, Hou BY, Wang MX (2012) Chem Commun (Camb) 48:11458–11460CrossRefGoogle Scholar
  30. 30.
    Breberina LM, Milčić MK, Nikolić MR, Stojanović SĐ (2015) J Biol Inorg Chem 20:475–485CrossRefPubMedGoogle Scholar
  31. 31.
    Zlatović MV, Borozan SZ, Nikolić MR, Stojanović SĐ (2015) RSC Adv 5:38361–38372CrossRefGoogle Scholar
  32. 32.
    Sievers SA, Karanicolas J, Chang HW, Zhao A, Jiang L, Zirafi O, Stevens JT, Munch J, Baker D, Eisenberg D (2011) Nature 475:96–100CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Burke PA, DeNardo SJ, Miers LA, Lamborn KR, Matzku S, DeNardo GL (2002) Cancer Res 62:4263–4272PubMedGoogle Scholar
  34. 34.
    Parlati F, Lee SJ, Aujay M, Suzuki E, Levitsky K, Lorens JB, Micklem DR, Ruurs P, Sylvain C, Lu Y, Shenk KD, Bennett MK (2009) Blood 114:3439–3447CrossRefPubMedGoogle Scholar
  35. 35.
    Smith Y, Wichmann T, Factor SA, DeLong MR (2012) Neuropsychopharmacology 37:213–246CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Turner EH, Blackwell AD (2005) Med Hypotheses 65:138–144CrossRefPubMedGoogle Scholar
  37. 37.
    Wang Q, Parrish AR, Wang L (2009) Chem Biol 16:323–336CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Ai HW, Shen W, Sagi A, Chen PR, Schultz PG (2011) ChemBioChem 12:1854–1857CrossRefPubMedGoogle Scholar
  39. 39.
    Kessler B, Michielin O, Blanchard CL, Apostolou I, Delarbre C, Gachelin G, Gregoire C, Malissen B, Cerottini JC, Wurm F, Karplus M, Luescher IF (1999) J Biol Chem 274:3622–3631CrossRefPubMedGoogle Scholar
  40. 40.
    Wang J, Xie J, Schultz PG (2006) J Am Chem Soc 128:8738–8739CrossRefPubMedGoogle Scholar
  41. 41.
    Lemke EA, Summerer D, Geierstanger BH, Brittain SM, Schultz PG (2007) Nat Chem Biol 3:769–772CrossRefPubMedGoogle Scholar
  42. 42.
    Gfeller D, Michielin O, Zoete V (2013) Nucleic Acids Res 41:D327–D332CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Rose PW, Beran B, Bi C, Bluhm WF, Dimitropoulos D, Goodsell DS, Prlic A, Quesada M, Quinn GB, Westbrook JD, Young J, Yukich B, Zardecki C, Berman HM, Bourne PE (2011) Nucleic Acids Res 39:D392–D401CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Word JM, Lovell SC, Richardson JS, Richardson DC (1999) J Mol Biol 285:1735–1747CrossRefPubMedGoogle Scholar
  45. 45.
    Accelrys Software Inc. (2014) Discovery Studio Visualizer, Release 4.1. Accelrys Software Inc., San DiegoGoogle Scholar
  46. 46.
    Jackson MR, Beahm R, Duvvuru S, Narasimhan C, Wu J, Wang HN, Philip VM, Hinde RJ, Howell EE (2007) J Phys Chem B 111:8242–8249CrossRefPubMedGoogle Scholar
  47. 47.
    Schrödinger Release 2015-1: Jaguar, version 8.7. Schrödinger, LLC, New York, NY, 2015Google Scholar
  48. 48.
    Dunning TH (1989) J Chem Phys 90:1007CrossRefGoogle Scholar
  49. 49.
    Clark T, Chandrasekhar J, Spitznagel GW, Schleyer PVR (1983) J Comput Chem 4:294–301CrossRefGoogle Scholar
  50. 50.
    Bochevarov AD, Harder E, Hughes TF, Greenwood JR, Braden DA, Philipp DM, Rinaldo D, Halls MD, Zhang J, Friesner RA (2013) Int J Quantum Chem 113:2110–2142CrossRefGoogle Scholar
  51. 51.
    Riley KE, Platts JA, Řezáč J, Hobza P, Hill JG (2012) J Phys Chem A 116:4159–4169CrossRefPubMedGoogle Scholar
  52. 52.
    Deng Y, Roux B (2009) J Phys Chem B 113:2234–2246CrossRefPubMedGoogle Scholar
  53. 53.
    Gumbart JC, Roux B, Chipot C (2013) J Chem Theory Comput 9:794–802CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Čeřný J, Hobza P (2007) Phys Chem Chem Phys 9:5291–5303CrossRefPubMedGoogle Scholar
  55. 55.
    Du QS, Wang QY, Du LQ, Chen D, Huang RB (2013) Chem Cent J 7:92CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Ballester P (2013) Acc Chem Res 46:874–884CrossRefPubMedGoogle Scholar
  57. 57.
    Bauza A, Mooibroek TJ, Frontera A (2016) CrystEngComm 18:10–23CrossRefGoogle Scholar
  58. 58.
    Kabsch W, Sander C (1983) Biopolymers 22:2577–2637CrossRefPubMedGoogle Scholar
  59. 59.
    Gromiha MM, Oobatake M, Kono H, Uedaira H, Sarai A (1999) Protein Eng 12:549–555CrossRefPubMedGoogle Scholar
  60. 60.
    Dosztanyi Z, Fiser A, Simon I (1997) J Mol Biol 272:597–612CrossRefPubMedGoogle Scholar
  61. 61.
    Dosztanyi Z, Magyar C, Tusnady G, Simon I (2003) Bioinformatics 19:899–900CrossRefPubMedGoogle Scholar
  62. 62.
    Cozzi F, Cinquini M, Annunziata R, Dwyer T, Siegel JS (1992) J Am Chem Soc 114:5729–5733CrossRefGoogle Scholar
  63. 63.
    Stojanović SĐ, Isenović ER, Zarić BL (2012) Amino Acids 43:1535–1546CrossRefGoogle Scholar
  64. 64.
    Garau C, Quiňonero D, Frontera A, Ballester P, Costa A, Deyà PM (2005) J Phys Chem A 109:9341–9345CrossRefPubMedGoogle Scholar
  65. 65.
    Bartlett GJ, Porter CT, Borkakoti N, Thornton JM (2002) J Mol Biol 324:105–121CrossRefPubMedGoogle Scholar
  66. 66.
    Malkov SN, Živković MV, Beljanski MV, Hall MB, Zarić SD (2008) J Mol Model 14:769–775CrossRefPubMedGoogle Scholar
  67. 67.
    Magyar C, Gromiha MM, Pujadas G, Tusnady GE, Simon I (2005) Nucleic Acids Res 33:W303–W305CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Dumas J-M, Peurichard H, Gomel MJ (1978) Chem Res (S) 1:54–57Google Scholar
  69. 69.
    Brinck T, Murray JS, Politzer P (1992) Int J Quantum Chem 44(Suppl. 19):57–64CrossRefGoogle Scholar
  70. 70.
    Clark T, Hennemann M, Murray JS, Politzer P (2007) J Mol Model 13:291–296CrossRefPubMedGoogle Scholar
  71. 71.
    Politzer P, Murray JS, Clark T (2010) Phys Chem Chem Phys 12:7748–7757CrossRefPubMedGoogle Scholar
  72. 72.
    Riley KE, Murray JS, Fanfrlik J, Řezáč J, Sola RJ, Concha MC, Ramos FM, Politzer P (2011) J Mol Model 17:3309–3318CrossRefPubMedGoogle Scholar
  73. 73.
    Auffinger P, Hays FA, Westhof E, Ho PS (2004) Proc Natl Acad Sci USA 101:16789–16794CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Alkorta I, Blanco F, Deyà P, Elguero J, Estarellas C, Frontera A, Quiňonero D (2010) Theor Chem Acc 126:1–14CrossRefGoogle Scholar
  75. 75.
    Politzer P, Murray JS, Clark T (2013) Phys Chem Chem Phys 15:11178–11189CrossRefPubMedGoogle Scholar
  76. 76.
    Estarellas C, Frontera A, Quiňonero D, Deyà PM (2011) ChemPhysChem 12:2742–2750CrossRefPubMedGoogle Scholar
  77. 77.
    Borozan SZ, Stojanović SĐ (2013) Comput Biol Chem 47:231–239CrossRefPubMedGoogle Scholar
  78. 78.
    Lu Y, Liu Y, Li H, Zhu X, Liu H, Zhu W (2012) J Phys Chem A 116:2591–2597CrossRefPubMedGoogle Scholar

Copyright information

© SBIC 2016

Authors and Affiliations

  • Sunčica Z. Borozan
    • 1
  • Mario V. Zlatović
    • 2
  • Srđan Đ. Stojanović
    • 3
    Email author
  1. 1.Department of Chemistry, Faculty of Veterinary MedicineUniversity of BelgradeBelgradeSerbia
  2. 2.Faculty of ChemistryUniversity of BelgradeBelgradeSerbia
  3. 3.ICTM-Department of ChemistryUniversity of BelgradeBelgradeSerbia

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