Theoretical Chemistry Accounts

, 135:260 | Cite as

A theoretical model of the interaction between phosphates in the ATP molecule and guanidinium systems

  • Cristina TrujilloEmail author
  • Viola Previtali
  • Isabel Rozas
Regular Article


In order to understand the interaction between adenosine-5′-triphosphate (ATP) and guanidinium, as recently hypothesized in protein kinase type III inhibitors, a theoretical study has been carried out. First, the intrinsic interactions established between these two systems were studied using a model of ATP; thus, the interactions between a phosphate anion and differently substituted phenylguanidinium cations have been analysed. Then, considering the most stable complexes found with this simplified model, those formed between the phosphate groups of ATP and diaromatic guanidinium derivatives have been studied. All the calculations have been performed using ab initio MP2/6-311++G(d,p)//MP2/6-31+G(d,p) computational level utilizing the polarizable continuum model mimicking water solvation. Besides, only for ATP complexes the geometry optimization has been modified, and thus, DFT-D calculations with the ωB97XD functional were carried out. The Atoms in Molecules analysis of the electron density, natural bond orbital second-order orbital energies and electron density shift maps have been used to better understand the intermolecular interactions.


Guanidinium cation Non-covalent interactions Hydrogen bond Weak interactions QCT 



Thanks are given to the School of Chemistry at Trinity College Dublin for postgraduate support (V.P.) and to the Irish Centre for High-End Computing (ICHEC) and the Trinity Centre for High-Performance Computing (TCHPC) for the provision of computational facilities. We are indebted to Dr. Goar Sánchez from the UCD School of Chemistry, for the AIM analysis and helpful discussions.

Supplementary material

214_2016_2012_MOESM1_ESM.docx (2.6 mb)
Supplementary material 1 (DOCX 2700 kb)


  1. 1.
    Klebl B, Muller G, Hamacher M, Mannhold R, Kubinyi H, Folkers G (2011) Protein kinases as drug targets. Wiley, HobokenCrossRefGoogle Scholar
  2. 2.
    O’Hare T, Eide CA, Deininger MW (2008) Expert Opin Investig Drugs 17:865–878CrossRefGoogle Scholar
  3. 3.
    Schenone S, Brullo C, Botta M (2010) Curr Med Chem 17:1220–1245CrossRefGoogle Scholar
  4. 4.
    Diez-Cecilia E, Kelly B, Perez C, Zisterer DM, Nevin DK, Lloyd DG, Rozas I (2014) Eur J Med Chem 81:427–441CrossRefGoogle Scholar
  5. 5.
    Iacob RE, Zhang J, Gray NS, Engen JR (2011) PLoS ONE 6:e15929CrossRefGoogle Scholar
  6. 6.
    Khateb M, Ruimi N, Khamisie H, Najajreh Y, Mian A, Metodieva A, Ruthardt M, Mahajna J (2012) BMC Cancer 12:563CrossRefGoogle Scholar
  7. 7.
    Zhang J, Adrian FJ, Jahnke W, Cowan-Jacob SW, Li AG, Iacob RE, Sim T, Powers J, Dierks C, Sun F, Guo GR, Ding Q, Okram B, Choi Y, Wojciechowski A, Deng X, Liu G, Fendrich G, Strauss A, Vajpai N, Grzesiek S, Tuntland T, Liu Y, Bursulaya B, Azam M, Manley PW, Engen JR, Daley GQ, Warmuth M, Gray NS (2010) Nature 463:501–506CrossRefGoogle Scholar
  8. 8.
    Li C, Ma N, Wang Y, Wang Y, Chen G (2014) J Phys Chem B 118:1273–1287CrossRefGoogle Scholar
  9. 9.
    Yang LJ, Zou J, Xie HZ, Li LL, Wei YQ, Yang SY (2009) PLoS ONE 4:e8470CrossRefGoogle Scholar
  10. 10.
    Bartlett S, Beddard GS, Jackson RM, Kayser V, Kilner C, Leach A, Nelson A, Oledzki PR, Parker P, Reid GD, Warriner SL (2005) J Am Chem Soc 127:11699–11708CrossRefGoogle Scholar
  11. 11.
    Golubovskaya VM, Ho B, Zheng M, Magis A, Ostrov D, Cance WG (2013) Anticancer Agents Med Chem 13:546–554CrossRefGoogle Scholar
  12. 12.
    Ubersax JA, Ferrell JE Jr (2007) Nat Rev Mol Cell Biol 8:530–541CrossRefGoogle Scholar
  13. 13.
    Volkamer A, Eid S, Turk S, Jaeger S, Rippmann F, Fulle S (2015) J Chem Inf Model 55:538–549CrossRefGoogle Scholar
  14. 14.
    Yusufaly TI, Li Y, Singh G, Olson WK (2014) J Chem Phys 141:165102CrossRefGoogle Scholar
  15. 15.
    Kataev EA, Müller C, Kolesnikov GV, Khrustalev VN (2014) Eur J Org Chem 2014:2747–2753CrossRefGoogle Scholar
  16. 16.
    Jin Y, Molt RW Jr, Waltho JP, Richards NG, Blackburn GM (2016) Angew Chem Int Ed Engl 55:3318–3322CrossRefGoogle Scholar
  17. 17.
    Pereira CA, Alonso GD, Ivaldi S, Silber AM, Alves MJ, Torres HN, Flawia MM (2003) FEBS Lett 554:201–205CrossRefGoogle Scholar
  18. 18.
    Andrews LD, Graham J, Snider MJ, Fraga D (2008) Comp Biochem Physiol B: Biochem Mol Biol 150:312–319CrossRefGoogle Scholar
  19. 19.
    Ellington WR (2001) Annu Rev Physiol 63:289–325CrossRefGoogle Scholar
  20. 20.
    Uda K, Fujimoto N, Akiyama Y, Mizuta K, Tanaka K, Ellington WR, Suzuki T (2006) Comp Biochem Physiol Part D Genomics Proteomics 1:209–218CrossRefGoogle Scholar
  21. 21.
    Kato Y, Conn MM, Rebek J Jr (1994) J Am Chem Soc 116:3279–3284CrossRefGoogle Scholar
  22. 22.
    Best MD, Tobey SL, Anslyn EV (2003) Coord Chem Rev 240:3–15CrossRefGoogle Scholar
  23. 23.
    Schug KA, Lindner W (2005) Chem Rev 105:67–114CrossRefGoogle Scholar
  24. 24.
    Blondeau P, Segura M, Perez-Fernandez R, de Mendoza J (2007) Chem Soc Rev 36:198–210CrossRefGoogle Scholar
  25. 25.
    Rozas I, Kruger PE (2005) J Chem Theory Comput 1:1055–1062CrossRefGoogle Scholar
  26. 26.
    Blanco F, Kelly B, Alkorta I, Rozas I, Elguero J (2011) Chem Phys Lett 511:129–134CrossRefGoogle Scholar
  27. 27.
    Kelly B, Sánchez-Sanz G, Blanco F, Rozas I (2012) Comput Theor Chem 998:64–73CrossRefGoogle Scholar
  28. 28.
    Rozas I, Sánchez-Sanz G, Alkorta I, Elguero J (2013) J Phys Org Chem 26:378–385CrossRefGoogle Scholar
  29. 29.
    Blanco F, Kelly B, Sánchez-Sanz G, Trujillo C, Alkorta I, Elguero J, Rozas I (2013) J Phys Chem B 117:11608–11616CrossRefGoogle Scholar
  30. 30.
    Marin-Luna M, Sanchez-Sanz G, O’Sullivan P, Rozas I (2014) J Phys Chem A 118:5540–5547CrossRefGoogle Scholar
  31. 31.
    Møller C, Plesset MS (1934) Phys Rev 46:618–622CrossRefGoogle Scholar
  32. 32.
    Frisch MJ, Pople JA, Binkley JS (1984) J Chem Phys 80:3265–3269CrossRefGoogle Scholar
  33. 33.
    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 JA Jr, 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 Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09, Revision E.01. Gaussian Inc, Wallingford CTGoogle Scholar
  34. 34.
    Reed AE, Curtiss LA, Weinhold F (1988) Chem Rev 88:899–926CrossRefGoogle Scholar
  35. 35.
    Popelier PLA (2012) Quantum chemical topology in drug design. In: Banting L, Clark T (eds) RSC drug discovery series No. 20: drug design strategies: computational techniques and applications, vol 6. Royal Society of Chemistry, Great Britain, pp 120–163Google Scholar
  36. 36.
    Popelier PLA (2005) Quantum chemical topology: on bonds and potential. In: Wales DJ (ed) Intermolecular forces and clusters I, vol 115. Springer, Heidelberg, pp 1–56Google Scholar
  37. 37.
    Bader RFW (1990) Atoms in molecules: a quantum theory. Clarendon Press, OxfordGoogle Scholar
  38. 38.
    Keith TA (2011) 11.10.16 edn., 2011, pp. TK Gristmill Software,( Scholar
  39. 39.
    Stockbridge RB, Wolfenden R (2009) J Biol Chem 284:22747–22757CrossRefGoogle Scholar
  40. 40.
    O’Neil MJ (2006) The Merck index—an encyclopedia of chemicals, drugs, and biologicals. Whitehouse Station,WMerck and Co., Inc., New YorkGoogle Scholar
  41. 41.
    Calculator Plugins were used for structure property prediction and calculation, Marvin 6.0.3, 2013, ChemAxon
  42. 42.
    Sanchez-Sanz G, Alkorta I, Elguero J (2011) Mol Phys 109:2543–2552CrossRefGoogle Scholar
  43. 43.
    Sanchez-Sanz G, Trujillo C, Alkorta I, Elguero J (2012) ChemPhysChem 13:496–503CrossRefGoogle Scholar
  44. 44.
    Sanchez-Sanz G, Trujillo C, Alkorta I, Elguero J (2014) Phys Chem Chem Phys 16:15900–15909CrossRefGoogle Scholar
  45. 45.
    Bauzá A, Alkorta I, Frontera A, Elguero J (2013) J Chem Theory Comput 9:5201–5210CrossRefGoogle Scholar
  46. 46.
    Alkorta I, Elguero J, Solimannejad M (2014) J Phys Chem A 118:947–953CrossRefGoogle Scholar
  47. 47.
    Sánchez-Sanz G, Trujillo C, Alkorta I, Elguero J (2012) Comput Theor Chem 991:124–133CrossRefGoogle Scholar
  48. 48.
    Matta CF, Arabi AA, Keith TA (2007) J Phys Chem A 111:8864–8872CrossRefGoogle Scholar
  49. 49.
    Arabi AA, Matta CF (2009) J Phys Chem A 113:3360–3368CrossRefGoogle Scholar
  50. 50.
    Arabi AA, Matta CF (2010) Energy richness of ATP in terms of atomic energies: a first step. In: Matta CF (ed) Quantum biochemistry: electronic structure and biological activity, vol 1, chap 15. Wiley-VCH, Weinheim, pp 473–498Google Scholar
  51. 51.
    Rozas I (2007) Phys Chem Chem Phys 9:2782–2790CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.School of Chemistry, Trinity Biomedical Sciences InstituteTrinity College DublinDublin 2Ireland

Personalised recommendations