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Ab initio simulations of Cu binding sites on the N-terminal region of prion protein

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The human prion protein binds Cu2+ ions in the octarepeat domain of the N-terminal tail up to full occupancy at pH 7.4. Recent experiments have shown that the HGGG octarepeat subdomain is responsible for holding the metal bound in a square-planar configuration. By using first principle ab initio molecular dynamics simulations of the Car–Parrinello type, the coordination of copper to the binding sites of the prion protein octarepeat region is investigated. Simulations are carried out for a number of structured binding sites. Results for the complexes Cu(HGGGW)(wat), Cu(HGGG), and [Cu(HGGG)]2 are presented. While the presence of a Trp residue and a water molecule does not seem to affect the nature of the copper coordination, high stability of the bond between copper and the amide nitrogen of deprotonated Gly residues is confirmed in all cases. For the more interesting [Cu(HGGG)]2 complex, a dynamically entangled arrangement of the two domains with exchange of amide nitrogen bonds between the two copper centers emerges, which is consistent with the short Cu–Cu distance observed in experiments at full copper occupancy.

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  1. 1.

    Stahl N, Borchelt DR, Hsiao K, Prusiner SB (1987) Cell 51:229–240

  2. 2.

    Bueler H, Aguzzi A, Sailer A, Greiner RA, Autensried P, Aguet M, Weissmann C (1993) Cell 73:1339–1347

  3. 3.

    Prusiner SB (1997) Science 278:245–251

  4. 4.

    Pan KM, Baldwin M, Nguyen J, Gasset M, Serban M, Serban A, Groth D, Mehlhorn I, Huang Z, Fletterick RJ, Cohen FE, Prusiner SB (1993) Proc Natl Acad Sci USA 90:10962–10966

  5. 5.

    Chiesa R, Drisaldi B, Quaglio E, Migheli A, Piccardo P, Ghetti B, Harris DA (2000) Proc Natl Acad Sci USA 97:5574–5579

  6. 6.

    Chiesa R, Piccardo P, Quaglio E, Drisaldi B, Si-Hoe SL, Takao M, Ghetti B, Harris DA (2003) J Virol 77:7611–7622

  7. 7.

    Nunziante M, Gilch S, Schatzl HM (2003) J Biol Chem 278:3726–3734

  8. 8.

    McKinley MP, Meyer RK, Kenaga L, Rahbar F, Serban RCA, Prusiner SB (1991) J Virol 65:1340–1351

  9. 9.

    Brown DR, Qin K, Herms JW, Madlung A, Manson J, Strome R, Fraser PE, Kruck T, von Bohlen A, Sculz-Schaeffer W, Giese A, Westaway D, Kretzschmar H (1997) Nature 390:684–687

  10. 10.

    Stockel J, Safar J, Wallace AC, Cohen FE, Prusiner SB (1998) Biochemistry 37:7185–7193

  11. 11.

    Pauly PC, Harris DA (1998) J Biol Chem 273:33107–33110

  12. 12.

    Brown LR, Harris DA (2003) J Neurochem 87:353–363

  13. 13.

    Viles JH, Cohen FE, Prusiner SB, Goodin DB, Wright PE, Dyson HJ (1999) Proc Natl Acad Sci USA 96:2042–2047

  14. 14.

    Pan KM, Stahl N, Prusiner SB (1992) Protein Sci 1:1343–1352

  15. 15.

    Morante S, Gonzalez-Iglesias R, Potrich C, Meneghini C, Meyer-Klaucke W, Menestrina G, Gasset M (2004) J Biol Chem 279:11753–11759

  16. 16.

    Hornshaw MP, McDermott JR, Candy JM (1995) Biochem Biophys Res Commun 207:621–629

  17. 17.

    Hornshaw MP, McDermott JR, Candy JM, Lakey JH (1995) Biochem Biophys Res Commun 214:993–999

  18. 18.

    Burns CS, Aronoff-Spencer E, Legname G, Prusiner SB, Antholine WE, Gerfen GJ, Peisach J, Millhauser GL (2003) Biochemistry 42:6794–6803

  19. 19.

    Hasnain SS, Murphy LM, Grossmann RWSJG, Clarke AR, Jackson GS, Collinge J (2001) J Mol Biol 311:467–473

  20. 20.

    Cereghetti GM, Schweiger A, Glockshuber R, van Doorslaer S (2001) Biophys J 81:516–525

  21. 21.

    Kramer ML, Kratzin HD, Schmidt B, Windl ARO, Liemann S, Hornemann S, Kretzschmar H (2001) J Biol Chem 276:16711–16719

  22. 22.

    Chattopadhyay M, Walter ED, Newell DJ, Jackson PJ, Aronoff-Spencer E, Peisach J, Gerfen GJ, Bennett B, Antholine WE, Millhauser GL (2005) J Am Chem Soc 127:12647–12656

  23. 23.

    Millhauser GL (2004) Acc Chem Res 37:79–85

  24. 24.

    Thompsett AR, Abdelraheim SR, Daniels M, Brown DR (2005) J Biol Chem 280:42750–42758

  25. 25.

    Gaggelli E, Kozlowski H, Valensin D, Valensin G (2006) Chem Rev 106:1995–2044

  26. 26.

    Jackson GS, Murray I, Hosszu LLP, Gibbs N, Waltho JP, Clarke AR, Colling J (2001) Proc Natl Acad Sci USA 98:8531–8535

  27. 27.

    Jones CE, Abdelraheim SR, Brown DR, Viles JH (2004) J Biol Chem 279:32018–32027

  28. 28.

    Burns CS, Aronoff-Spencer E, Dunham CM, Lario P, Avdievich NI, Antholine WE, Olmstead MM, Vrielink A, Gerfen GJ, Peisach J, Scott WG, Millhauser GL (2002) Biochemistry 41:3991–4001

  29. 29.

    Zahn R (2003) J Mol Biol 334:477–488

  30. 30.

    Garnett AP, Viles JH (2003) J Biol Chem 278:6795–6802

  31. 31.

    Sigel H, Martin RB (1982) Chem Rev 82:385–426

  32. 32.

    Sportelli L, Neubacher H, Lohmann W (1977) Biophys Struct Mech 3:317–326

  33. 33.

    Pushie MJ, Rauk A (2003) J Biol Inorg Chem 8:53–65

  34. 34.

    Franzini E, De Gioia L, Fantucci P, Zampella G (2003) Inorg Chem Commun 6:650–653

  35. 35.

    Car R, Parrinello M (1985) Phys Rev Lett 55:2471–2474

  36. 36.

    Carloni P, Rothlisberger U, Parrinello M (2002) Acc Chem Res 35:455–465

  37. 37.

    Baroni S, Dal Corso A, de Gironcoli S, Giannozzi P, Cavazzoni C, Ballabio G, Scandolo S, Chiarotti G, Focher P, Pasquarello A, Laasonen K, Trave A, Car R, Marzari N, Kokalj A http://www.pwscf.org

  38. 38.

    Vanderbilt D (1990) Phys Rev B 41:7892–7895

  39. 39.

    Laasonen K, Pasquarello A, Car R, Lee C, Vanderbilt D (1993) Phys Rev B 47:10142–10153

  40. 40.

    Perdew JP, Burke K, Ernzerhof M (1996) Phys Rev Lett 77:3865–3868

  41. 41.

    Nosé S (1984) Molec Phys 52:255–268

  42. 42.

    Frenkel D, Smit B (1996) Understanding molecular simulation. Academic, San Diego

  43. 43.

    La Penna G, Morante S, Perico A, Rossi GC (2004) J Chem Phys 121:10725–10741

  44. 44.

    Cornell WD, Cieplak P, Bayly CI, Gould IR, Merz KMJ, Ferguson DM, Spellmeyer DC, Fox T, Caldwell JW, Kollman PA (1995) J Am Chem Soc 117:5179–5197

  45. 45.

    Smith DR (1998) Coord Chem Rev 172:457–573

  46. 46.

    Young D (2001) Computational chemistry: a practical guide for applying techniques to real world problems. Wiley, New York

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The computations were performed on Linux clusters at the CINECA consortium (Bologna), E. Fermi Research Center (Roma), European Centre for Theoretical Studies (Trento), and Magnetic Resonance Center (Florence). The authors thank P. Giannozzi (Scuola Normale Superiore, Pisa) and C. Cavazzoni (CINECA) for many useful suggestions in handling the ESPRESSO code. S.F. is grateful for financial support from the project MUR-Firb no. RBNE03P83.

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Correspondence to Giovanni La Penna.

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Furlan, S., La Penna, G., Guerrieri, F. et al. Ab initio simulations of Cu binding sites on the N-terminal region of prion protein. J Biol Inorg Chem 12, 571–583 (2007). https://doi.org/10.1007/s00775-007-0218-x

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  • Prion protein
  • Copper
  • Computer simulations
  • Ab initio molecular dynamics