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Study of the docking of competitive inhibitors at a model of tyrosinase active site: Insights from joint broken-symmetry/spin-flip DFT computations and ELF topological analysis

  • A. de la Lande
  • J. Maddaluno
  • O. Parisel
  • T. A. Darden
  • J. -P. Piquemal
Article

Abstract

Following our previous study (Piquemal et al., 2003), we present here a DFT study of the inhibition of the Tyrosinase enzyme. Broken-symmetry DFT computations are supplemented with Spin-Flip TD-DFT calculations, which, for the first time, are applied to such a dicopper enzyme. The chosen biomimetic model encompasses a dioxygen molecule, two Cu(II) cations, and six imidazole rings. The docking energy of a natural substrate, namely phenolate, together with those of several inhibitor and non-inhibitor compounds, are reported and show the ability of the model to rank the most potent inhibitors in agreement with experimental data. With respect to broken-symmetry calculations, the Spin-Flip TD-DFT approach reinforces the possibility for theory to point out potent inhibitors: the need for the deprotonation of the substrates, natural or inhibitors, is now clearly established. Moreover, Electron Localization Function (ELF) topological analysis computations are used to deeply track the particular electronic distribution of the Cu-O-Cu three-center bonds involved in the enzymatic Cu2O2 metallic core (Piquemal and Pilmé, 2006). It is shown that such bonds exhibit very resilient out-of-plane density expansions that play a key role in docking interactions: their 3D-orientation could be the topological electronic signature of oxygen activation within such systems.

Key words

Density Functional Theory Spin-Flip TD-DFT copper oxygenase tyrosinase competitive inhibition 

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References

  1. [1]
    Becke, A.D. 1988. Correlation energy of an inhomogeneous electron gas: A coordinate-space model. J Chem Phys 88, 1053–1062.CrossRefGoogle Scholar
  2. [2]
    Becke, A.D., Edgecombe, K.E. 1990. A simple measure of electron localization in atomic and molecular systems. J Chem Phys 92, 5397–5403.CrossRefGoogle Scholar
  3. [3]
    Bubacco, L., Vijgenboom, E., Gobin, C., Tepper, A.W.J.W., Salgado, J., Canters, G., 2000. Kinetic and paramagnetic NMR investigations of the inhibition of Streptomyces Antibioticus tyrosinase. J Mol Cat B: Enzymatic 8, 27–35.CrossRefGoogle Scholar
  4. [4]
    Conrad, J.S., Dawso, S.R., Hubbard, E.R., Meyers, T.E., Strothkamp, K.G. 1994. Inhibitor binding to the binuclear active site of tyrosinase: Temperature, pH, and solvent deuterium isotope effects. Biochem 33, 5739–5744.CrossRefGoogle Scholar
  5. [5]
    Cramer, C.J., Włoch, M., Piecuch, P., Puzzarini, C., Gagliardi, L. 2006. Theoretical models on the Cu2O2 torture track: Mechanistic implications for oxytyrosinase and small-molecule analogues. J Phys Chem A 110, 1991–2004.CrossRefPubMedGoogle Scholar
  6. [6]
    Decker, H., Schweikardt, T., Tuczek, F. 2006. Angew. Chemie Int. Ed., 4545–4546.Google Scholar
  7. [7]
    Decker, H., Tuczek, F. 2000. Tyrosinase/catecholoxidase activity of hemocyanins: structural basis and molecular mechanism. Trends in Biochemical Sciences 25, 392–397.CrossRefPubMedGoogle Scholar
  8. [8]
    de la Lande, A., Gérard, H., Parisel, O. 2008a. How to optimize a C-H cleavage with a mononuclear copper-dioxygen adduct? Int J Quant Chem 108 1898–1904.CrossRefGoogle Scholar
  9. [9]
    de la Lande, A., Moliner, V., Parisel, O. 2007. Singlet-triplet gaps in large multireference systems: Spin-flip-driven alternatives for bioinorganic modeling. J Chem Phys 126, 035102.CrossRefPubMedGoogle Scholar
  10. [10]
    de la Lande, A., Parisel, O., Gérard, H., Moliner, V., Reinaud, O. 2008b. Theoretical exploration on the oxidative properties of a [(tren)CuO2]+ adduct relevant to copper monoxygenase enzymes: insights into the competitive dehydrogenation vs. hydroxylation reactive pathways. Chem Eur J 14, 6465–6473.CrossRefGoogle Scholar
  11. [11]
    de la Lande, A., Salahub, D., Moliner, V., Gérard, H., Piquemal, J.-P., Parisel, O. 2009. Dioxygen activation by mononuclear copper enzymes: Insights from a tripodal ligand mimicking their CuM coordination sphere. Inorg Chem 48, 7003–7005.CrossRefPubMedGoogle Scholar
  12. [12]
    Diedrich, C., Deeth, R.J. 2008. On the performance of Ligand Field Molecular Mechanics for model complexes containing the peroxido-bridged [Cu2O2]2+ center. Inorg Chem 47, 2494–2506.CrossRefPubMedGoogle Scholar
  13. [13]
    Dugas, H. 1989. Bioorganic Chemistry, A Chemical Approach to Enzyme Action. Springer-Verlag, New-York.Google Scholar
  14. [14]
    Friedman, M. 1996. Food browning and its prevention: An overview. J Agric Food Chem 44, 31–653.Google Scholar
  15. [15]
    Gherman, B.F., Cramer, C.J. 2009. Quantum chemical studies of molecules incorporating a Cu2O22+ core. Coord Chem Rev 253, 723–753.CrossRefGoogle Scholar
  16. [16]
    Giebel, L.B. Tripathi, King, R.A., Spritz, R.A. 1991. A tyrosinase gene missense mutation in temperature-sensitive type I oculocutaneous albinism. A human homologue to the Siamese cat and the Himalayan mouse. J Clin Invest 87, 1119–1122.CrossRefPubMedGoogle Scholar
  17. [17]
    Gresh, N., Cisneros, G.A., Darden, T.A., Piquemal, J.-P. 2007. Anisotropic, polarizable molecular mechanics studies of inter-, intra-molecular interactions, and ligand-macromolecule complexes. A bottom-up strategy. J Chem Theory Comput 3, 1960–1986.CrossRefPubMedGoogle Scholar
  18. [18]
    Jaguar 4.1 2000. Schrodinger Inc., Portland OR, USA.Google Scholar
  19. [19]
    Jimenez, M., Chazarra, S., Escribano, J., Cabanes, J., Garcia-Carmona, F.J. 2001. Competitive inhibition of mushroom tyrosinase by 4-substituted benzaldehydes. Agric Food Chem 49, 4060–4063.CrossRefGoogle Scholar
  20. [20]
    Karlin, K.D., Lee, D-H., Obias, H.V., Humphreys, K.J. 1998. Copper-dioxygen complexes: functional models for proteins. Pure Appl Chem 70, 855–862.CrossRefGoogle Scholar
  21. [21]
    Kim, Y-J., Uyama, H. 2005. Tyrosinase inhibitors from natural and synthetic sources: structure, inhibition mechanism and perspective for the future. CMLS 62, 1707–1723.CrossRefPubMedGoogle Scholar
  22. [22]
    Kitajima, N., Morooka, Y. 1994. Copper-dioxygen complexes. Inorganic and bioinorganic perspectives. Chem Rev 94, 737–757.CrossRefGoogle Scholar
  23. [23]
    Krishnan, R., Binkley, J.S., Seeger, R., Pople, J.A. 1980. Self-consistent molecular orbital methods. A basis set for correlated wave functions. J Chem Phys 72, 650–654.CrossRefGoogle Scholar
  24. [24]
    Lee, C., Yang, W., Parr, R.G. 1988. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys Rev B 37, 785–789.CrossRefGoogle Scholar
  25. [25]
    Lerch, K. 1987. Molecular and active site structure of tyrosinase. Life Chem Rep 5, 221–234.Google Scholar
  26. [26]
    Lind, T., Siegbahn, P.E.M., Crabtree, R.H. 1999. A quantum chemical study of the mechanism of tyrosinase. J Phys Chem B 103, 1193–1202.CrossRefGoogle Scholar
  27. [27]
    Maddaluno, J., Faull, K.F. 1988. Inhibition of mushroom tyrosinase by 3-amino-L-tyrosine: molecular probing of the active site of the enzyme. Experientia 44, 885–887.CrossRefPubMedGoogle Scholar
  28. [28]
    Maeda, K., Fukuda, M. 1991. In vitro effectiveness of several whitening cosmetic components in human melanocytes. J Soc Cosmet Chem 42, 361–368.Google Scholar
  29. [29]
    Matoba, Y., Kumagai, T., Yamamoto, A., Yoshitsu, H., Sugiyama, M. 2006. Crystallographic evidence that the dinuclear copper center of tyrosinase is flexible during catalysis. J Biol Chem 281, 8981–8990.CrossRefPubMedGoogle Scholar
  30. [30]
    McLean, A.D., Chandler, G.S. 1980. Contracted Gaussian basis sets for molecular calculations. I. Second row atoms, Z=11–18. J Chem Phys 72, 5639–5648.CrossRefGoogle Scholar
  31. [31]
    Mirica, L.M., Rudd, D.J., Vance, M.A., Solomon, E.I., Hodgson, K.O., Hedman, B., Stack, T.D.P. 2006. µ — ν 2:νy-Peroxodicopper(II) complex with a secondary diamine ligand: a functional model of tyrosinase. J Am Chem Soc 128, 2654–2665.CrossRefPubMedGoogle Scholar
  32. [32]
    Murthy, N.N., Mahroof-Tahir, M., Karlin, K.D. 2001. Dicopper(I) complexes of unsymmetrical binucleating ligands and their dioxygen reactivities. Inorg Chem 40, 628–635.CrossRefPubMedGoogle Scholar
  33. [33]
    Neese, F. 2009. Prediction of molecular spectra and molecular properties with Density Functional Theory: From fundamental theory to exchange coupling. Coord Chem Rev 253, 526–563.CrossRefGoogle Scholar
  34. [34]
    Noury, S., Krokidis, X., Fuster, F., Silvi, B. 1999. Computational tools for the electron localization function topological analysis. Comput Chem 23, 597–604.CrossRefGoogle Scholar
  35. [35]
    Palavicini, S., Granata, A., Monzani, E., Casella, L. 2005. Hydroxylation of phenolic compounds by a peroxodicopper(II) complex: Further insight into the mechanism of tyrosinase. J Am Chem Soc 127, 18031–18036.CrossRefPubMedGoogle Scholar
  36. [36]
    Pilmé, J., Piquemal, J.-P. 2008. Advancing beyond charge analysis using the Electronic Localization Function: Chemically intuitive distribution of electrostatic moments. J Comput Chem 29, 1440–1449.CrossRefPubMedGoogle Scholar
  37. [37]
    Piquemal, J.-P, Maddaluno, J., Silvi B, Giessner-Prettre, C. 2003. Theoretical study of phenol and 2-aminophenol docking at a model of tyrosinase active site. New J Chem 27, 909–913.CrossRefGoogle Scholar
  38. [38]
    Piquemal, J.-P., Williams-Hubbard, B., Fey, N., Deeth, R.J., Gresh, N., Giessner-Prettre, C. 2003. Inclusion of the ligand field contribution in a polarizable molecular mechanics: SIBFA LF. J Comput Chem 24, 1963–1970.CrossRefPubMedGoogle Scholar
  39. [39]
    Piquemal, J.-P., Pilmé, J. 2006. Comments on the nature of the bonding in oxygenated dinuclear copper enzymes models. J Mol Struct: THEOCHEM 764, 77–86.CrossRefPubMedGoogle Scholar
  40. [40]
    Piquemal, J.-P., Pilmé, J., Parisel, O., Gérard, H, Fourré, I., Berg`es, J., Gourlaouen, C., de la Lande, A., van Severen, M.-C., Silvi, B. 2008. What can be learnt on biological or biomimetic systems with the topological analysis of the electron localization function? Int J Quant Chem 108, 1951–1969.CrossRefGoogle Scholar
  41. [41]
    Prezioso, J.A., Epperly, M.W., Wang, N., Bloomer, W.D. 1992. Effects of tyrosinase activity on the cytotoxicity of 4-S-cysteaminylphenol and N-acetyl-4-S-cysteaminylphenol in melanoma cells. Cancer Lett 63, 73–79.CrossRefPubMedGoogle Scholar
  42. [42]
    Rassolov, V., Pople, J.A., Ratner, M., Windus, T.L. 1998. 6-31G* basis set for atoms K through Zn. J Chem Phys 109, 1223–1229.CrossRefGoogle Scholar
  43. [43]
    Rode, M.F., Werner, H.J. 2005. Ab initio study of the O2 binding in dicopper complexes. Theor Chem Acc 114, 309–317.CrossRefGoogle Scholar
  44. [44]
    Ross, P.K., Solomon, E.I. 1991. An electronic structural comparison of copper-peroxide complexes of relevance to hemocyanin and tyrosinase active sites. J Am Chem Soc 113, 3246–3259.CrossRefGoogle Scholar
  45. [45]
    Shao, Y., Head-Gordon, M., Krylov, A.I. 2003. The spin-flip approach within time-dependent density functional theory: Theory and applications to diradicals. J Chem Phys 118, 4807–4818.CrossRefGoogle Scholar
  46. [46]
    Shao, Y., Molnar, L.F., Jung, Y., Kussmann, J., Ochsenfeld, C., Brown, S.T., Gilbert, A.T., Slipchenko, L.V., Levchenko, S.V., O’Neill, D.P., DiStasio, R.A. Jr, Lochan, R.C., Wang, T., Beran, G.J., Besley, N.A., Herbert, J.M., Lin, C.Y., Van Voorhis, T., Chien, S.H., Sodt, A., Steele, R.P., Rassolov, V.A., Maslen, P.E., Korambath, P.P., Adamson, R.D., Austin, B., Baker, J., Byrd, E.F., Dachsel H., Doerksen R.J., Dreuw, A., Dunietz, B.D., Dutoi, A.D., Furlani, T.R., Gwaltney, S.R., Heyden, A., Hirata, S., Hsu, C.P., Kedziora, G., Khalliulin, R.Z., Klunzinger, P., Lee, A.M., Lee, M.S., Liang, W., Lotan, I., Nair, N., Peters, B., Proynov, E.I., Pieniazek, P.A., Rhee, Y.M., Ritchie, J., Rosta, E., Sherrill, C.D., Simmonett, A.C., Subotnik, J.E., Woodcock, H.L. 3rd, Zhang W., Bell, A.T., Chakraborty, A.K., Chipman, D.M., Keil, F.J., Warshel, A., Hehre, W.J., Schaefer, H.F. 3rd, Kong, J., Krylov, A.I., Gill, P.M., Head-Gordon, M. 2006. Advances in methods and algorithms in a modern quantum chemistry program package. Phys Chem Chem Phys 8, 3172–3191.CrossRefPubMedGoogle Scholar
  47. [47]
    Silvi, B., Savin, A. 1994. Classification of chemical bonds based on topological analysis of electron localization functions. Nature 371, 683–686.CrossRefGoogle Scholar
  48. [48]
    Solomon, E.I., Chen, P., Metz, M., Lee, S.K., Palmer, A.E. 2001. Oxygen binding, activation, and reduction to water by copper proteins. Angew Chem Int Ed 40, 4570–4590.CrossRefGoogle Scholar
  49. [49]
    Tolman, W.B. 2006. Using synthetic chemistry to understand copper protein active sites: a personal perspective. J Biol Inorg Chem 11, 261–271.CrossRefPubMedGoogle Scholar
  50. [50]
    Volbeda, A., Hol, W.G.J. 1989. Crystal structure of hexameric haemocyanin from Panulirus interruptus refined at 3.2 Å resolution. J Mol Biol 209, 249–279.CrossRefPubMedGoogle Scholar
  51. [51]
    Wang, F., Ziegler, T. 2004. Time-dependent Density Functional Theory based on a noncollinear formulation of the exchange-correlation potential. J Chem Phys 121, 12191–12196.CrossRefPubMedGoogle Scholar
  52. [52]
    Xu, Y., Stokes, A.H., Freeman, W.M., Kumer, S.C., Vogt, B.A., Vrana, K.E. 1997. Tyrosinase mRNA is expressed in human substantia nigra. Mol Brain Res 45, 159–162.CrossRefPubMedGoogle Scholar

Copyright information

© International Association of Scientists in the Interdisciplinary Areas and Springer Berlin Heidelberg 2010

Authors and Affiliations

  • A. de la Lande
    • 1
    • 2
    • 3
  • J. Maddaluno
    • 4
  • O. Parisel
    • 1
    • 2
  • T. A. Darden
    • 5
  • J. -P. Piquemal
    • 1
    • 2
  1. 1.Laboratoire de Chimie ThéoriqueUPMC Univ. Paris 06, UMR 7616ParisFrance
  2. 2.Laboratoire de Chimie ThéoriqueCNRS, UMR 7616ParisFrance
  3. 3.Institute for Biocomplexity and InformaticsUniversity of CalgaryCalgaryCanada
  4. 4.Institut de Recherche en Chimie Organique Fine, UMR 6014 CNRSUniversité de RouenMont St Aignan CedexFrance
  5. 5.Laboratory of Structural BiologyNational Institute of Environmental Health SciencesResearch Triangle ParkUSA

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