Skip to main content

Advertisement

SpringerLink
Log in

Computational study of the binding of CuII to Alzheimer’s amyloid-β peptide: Do Aβ42 and Aβ40 bind copper in identical fashion?

  • Original Paper
  • Published:
JBIC Journal of Biological Inorganic Chemistry Aims and scope Submit manuscript

Abstract

One of the many hypotheses on the pathogenesis of Alzheimer’s disease is that the amyloid-β peptide (Aβ) binds CuII and can catalytically generate H2O2, leading to oxidative damage in brain tissues. For a molecular level understanding of such catalysis it is critical to know the structure of the Aβ–CuII complex precisely. Unfortunately, no high-resolution structure is available to date and there is considerable debate over the copper coordination environment with no clear consensus on which residues are directly bound to CuII. Considering all plausible isomers of the copper-bound Aβ42 and Aβ40 using a combination of density functional theory and classical molecular dynamics methods, we report an atomic resolution structure for each possible complex. We evaluated the relative energies of these isomeric structures and surprisingly found that Aβ42 and Aβ40 display very different binding modes, suggesting that shorter peptides that are truncated at the C-terminus may not be realistic models for understanding the chemistry of the most neurotoxic peptide, Aβ42.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

Aβ:

Amyloid-β peptide

AD:

Alzheimer’s disease

DFT:

Density functional theory

EPR:

Electron paramagnetic resonance

MD:

Molecular dynamics

MM:

Molecular mechanics

QM:

Quantum mechanical

References

  1. Varadarajan S, Yatin S, Aksenova M, Butterfield DA (2000) J Struct Biol 130:184–208

    Article  PubMed  CAS  Google Scholar 

  2. Pike CJ, Walencewicz AJ, Glabe CG, Cotman CW (1991) Brain Res 563:311–314

    Article  PubMed  CAS  Google Scholar 

  3. Hardy J, Selkoe DJ (2002) Science 297:353–356

    Article  PubMed  CAS  Google Scholar 

  4. Bush AI, Pettingell WH, Multhaup G, Paradis MD, Vonsattel JP, Gusella JF, Beyreuther K, Masters CL, Tanzi RE (1994) Science 265:1464–1467

    Article  PubMed  CAS  Google Scholar 

  5. White AR, Multhaup G, Maher F, Bellingham S, Camakaris J, Zheng H, Bush AI, Beyreuther K, Masters CL, Cappai R (1999) J Neurosci 19:9170–9179

    PubMed  CAS  Google Scholar 

  6. Atwood CS, Scarpa RC, Huang XD, Moir RD, Jones WD, Fairlie DP, Tanzi RE, Bush AI (2000) J Neurochem 75:1219–1233

    Article  PubMed  CAS  Google Scholar 

  7. Huang XD, Cuajungco MP, Atwood CS, Hartshorn MA, Tyndall JDA, Hanson GR, Stokes KC, Leopold M, Multhaup G, Goldstein LE, Scarpa RC, Saunders AJ, Lim J, Moir RD, Glabe C, Bowden EF, Masters CL, Fairlie DP, Tanzi RE, Bush AI (1999) J Biol Chem 274:37111–37116

    Article  PubMed  CAS  Google Scholar 

  8. Barnham KJ, Haeffner F, Ciccotosto GD, Curtain CC, Tew D, Mavros C, Beyreuther K, Carrington D, Masters CL, Cherny RA, Cappai R, Bush AI (2004) FASEB J 18:1427–1429

    PubMed  CAS  Google Scholar 

  9. Barnham KJ, McKinstry WJ, Multhaup G, Galatis D, Morton CJ, Curtain CC, Williamson NA, White AR, Hinds MG, Norton RS, Beyreuther K, Masters CL, Parker MW, Cappai R (2003) J Biol Chem 278:17401–17407

    Article  PubMed  CAS  Google Scholar 

  10. Rossjohn J, Cappai R, Feil SC, Henry A, McKinstry WJ, Galatis D, Hesse L, Multhaup G, Beyreuther K, Masters CL, Parker MW (1999) Nat Struct Biol 6:327–331

    Article  PubMed  CAS  Google Scholar 

  11. Karr JW, Akintoye H, Kaupp LJ, Szalai VA (2005) Biochemistry 44:5478–5487

    Article  PubMed  CAS  Google Scholar 

  12. Karr JW, Kaupp LJ, Szalai VA (2004) J Am Chem Soc 126:13534–13538

    Article  PubMed  CAS  Google Scholar 

  13. Syme CD, Nadal RC, Rigby SEJ, Viles JH (2004) J Biol Chem 279:18169–18177

    Article  PubMed  CAS  Google Scholar 

  14. Curtain CC, Ali F, Volitakis I, Cherny RA, Norton RS, Beyreuther K, Barrow CJ, Masters CL, Bush AI, Barnham KJ (2001) J Biol Chem 276:20466–20473

    Article  PubMed  CAS  Google Scholar 

  15. Raffa DF, Rauk A (2007) J Phys Chem B 111:3789–3799

    Article  PubMed  CAS  Google Scholar 

  16. Gomez-Balderas R, Raffa DF, Rickard GA, Brunelle P, Rauk A (2005) J Phys Chem A 109:5498–5508

    Article  PubMed  CAS  Google Scholar 

  17. Rickard GA, Gomez-Balderas R, Brunelle P, Raffa DF, Rauk A (2005) J Phys Chem A 109:8361–8370

    Article  PubMed  CAS  Google Scholar 

  18. Barnham KJ, Haeffner F, Ciccotosto GD, Curtain CC, Tew D, Masters CL, Chemy RA, Cappai R, Bush AI (2004) Neurobiol Aging 25:S544

    Article  Google Scholar 

  19. Haeffner F, Smith DG, Barnham KJ, Bush AI (2005) J Inorg Biochem 99:2403–2422

    Article  PubMed  CAS  Google Scholar 

  20. Baumketner A, Bernstein SL, Wyttenbach T, Bitan G, Teplow DB, Bowers MT, Shea J-E (2006) Protein Sci 15:420–428

    Article  PubMed  CAS  Google Scholar 

  21. Baumketner A, Bernstein SL, Wyttenbach T, Lazo ND, Teplow DB, Bowers MT, Shea J-E (2006) Protein Sci 15:1239–1247

    Article  PubMed  CAS  Google Scholar 

  22. Jang S, Shin S (2008) J Phys Chem B 112:3479–3484

    Article  PubMed  CAS  Google Scholar 

  23. Itoh SG, Okamoto Y (2008) J Phys Chem B 112:2767–2770

    Article  PubMed  CAS  Google Scholar 

  24. Shen L, Ji H-F, Zhang H-Y (2008) J Phys Chem B 112:3164–3167

    Article  PubMed  CAS  Google Scholar 

  25. Triguero L, Singh R, Prabhakar R (2008) J Phys Chem B 112:2159–2167

    Article  PubMed  CAS  Google Scholar 

  26. Jiao Y, Yang P (2007) J Phys Chem B 111:7646–7655

    Article  PubMed  CAS  Google Scholar 

  27. Li W, Zhang J, Su Y, Wang J, Qin M, Wang W (2007) J Phys Chem B 111:13814–13821

    Article  PubMed  CAS  Google Scholar 

  28. Rauk A (2008) Dalton Trans 1273–1282

  29. Dong X, Chen W, Mousseau N, Derreumaux P (2008) J Chem Phys 128:125108

    Article  PubMed  Google Scholar 

  30. Miura T, Suzuki K, Kohata N, Takeuchi H (2000) Biochemistry 39:7024–7031

    Article  PubMed  CAS  Google Scholar 

  31. Atwood CS, Perry G, Zeng H, Kato Y, Jones WD, Ling KQ, Huang XD, Moir RD, Wang DD, Sayre LM, Smith MA, Chen SG, Bush AI (2004) Biochemistry 43:560–568

    Article  PubMed  CAS  Google Scholar 

  32. Karr JW, Szalai VA (2007) J Am Chem Soc 129:3796–3797

    Article  PubMed  CAS  Google Scholar 

  33. Kim W, Hecht MH (2005) J Biol Chem. M505763200

  34. Bitan G, Kirkitadze MD, Lomakin A, Vollers SS, Benedek GB, Teplow DB (2003) Proc Natl Acad Sci USA 100:330–335

    Article  PubMed  CAS  Google Scholar 

  35. Parr RG, Yang W (1989) Density functional theory of atoms and molecules. Oxford University Press, New York

    Google Scholar 

  36. Schrödinger (2003) Jaguar 5.5. Schrödinger, Portland

  37. Becke AD (1988) Phys Rev A 38:3098–3100

    Article  PubMed  CAS  Google Scholar 

  38. Becke AD (1993) J Chem Phys 98:5648–5652

    Article  CAS  Google Scholar 

  39. Lee CT, Yang WT, Parr RG (1988) Phys Rev B 37:785–789

    Article  CAS  Google Scholar 

  40. Hay PJ, Wadt WR (1985) J Chem Phys 82:299–310

    Article  CAS  Google Scholar 

  41. Dunning TH (1989) J Chem Phys 90:1007–1023

    Article  CAS  Google Scholar 

  42. Marten B, Kim K, Cortis C, Friesner RA, Murphy RB, Ringnalda MN, Sitkoff D, Honig B (1996) J Phys Chem 100:11775–11788

    Article  CAS  Google Scholar 

  43. Marcus Y (1991) J Chem Soc Faraday Trans 87:2995–2999

    Article  CAS  Google Scholar 

  44. Tawa GJ, Topol IA, Burt SK, Caldwell RA, Rashin AA (1998) J Chem Phys 109:4852–4863

    Article  CAS  Google Scholar 

  45. Sciarretta KL, Gordon DJ, Petkova AT, Tycko R, Meredith SC (2005) Biochemistry 44:6003–6014

    Article  PubMed  CAS  Google Scholar 

  46. Crescenzi O, Tomaselli S, Guerrini R, Salvadori S, D’Ursi AM, Temussi PA, Picone D (2002) Eur J Biochem 269:5642–5648

    Article  PubMed  CAS  Google Scholar 

  47. Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ (2005) J Comput Chem 26:1701–1718

    Article  Google Scholar 

  48. Antzutkin ON, Leapman RD, Balbach JJ, Tycko R (2002) Biochemistry 41:15436–15450

    Article  PubMed  CAS  Google Scholar 

  49. Petkova AT, Ishii Y, Balbach JJ, Antzutkin ON, Leapman RD, Delaglio F, Tycko R (2002) Proc Natl Acad Sci USA 99:16742–16747

    Article  PubMed  CAS  Google Scholar 

  50. Esler WP, Stimson ER, Ghilardi JR, Lu Y-A, Felix AM, Vinters HV, Mantyh PW, Lee JP, Maggio JE (1996) Biochemistry 35:13914–13921

    Article  PubMed  CAS  Google Scholar 

  51. Berendsen HJC, Vanderspoel D, Vandrunen R (1995) Comput Phys Commun 91:43–56

    Article  CAS  Google Scholar 

  52. Huang XD, Atwood CS, Hartshorn MA, Multhaup G, Goldstein LE, Scarpa RC, Cuajungco MP, Gray DN, Lim J, Moir RD, Tanzi RE, Bush AI (1999) Biochemistry 38:7609–7616

    Article  PubMed  CAS  Google Scholar 

  53. Kowalik-Jankowska T, Ruta M, Wisniewska K, Lankiewicz L (2003) J Inorg Biochem 95:270–282

    Article  PubMed  CAS  Google Scholar 

  54. Schoneich C, Williams TD (2002) Chem Res Toxicol 15:717–722

    Article  PubMed  Google Scholar 

  55. Dong J, Atwood CS, Anderson VE, Siedlak SL, Smith MA, Perry G, Carey PR (2003) Biochemistry 42:2768–2773

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank NSF (0116050 and CHE-0645381) for financial support. We also thank the Research Corporation for a Cottrell Award (M.-H.B.), the Alfred P. Sloan Foundation for an Alfred P. Sloan Fellowship (M.-H.B) and Iris Klinkenberg for a Klinkenberg Award (Y.M.).

Author information

Authors and Affiliations

  1. Department of Chemistry and School of Informatics, Indiana University, Bloomington, IN, 47405, USA

    Yogita Mantri, Marco Fioroni & Mu-Hyun Baik

Authors
  1. Yogita Mantri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marco Fioroni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mu-Hyun Baik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mu-Hyun Baik.

Electronic supplementary material

Below is the link to the electronic supplementary material.

775_2008_403_MOESM1_ESM.pdf

Supplementary material. Sample correlation plot between the QM versus MM IR frequencies (cm−1) for the 3His–Asp complex (Fig. S1), computed energy components for the optimized structures of all copper complexes (Table S1), computed energy components for the optimized structures of the free ligands, CuII and H+ (Table S2), computed free energies for the deprotonation of serine and tyrosine (Table S3), topology tables for Cu-Aβ42 models (Table S4), Cartesian coordinates of QM models (Table S5), PDB coordinates of most populated conformers of Cu-Aβ42 complexes from 1ms MD simulations (Table S6), PDB coordinates of most populated conformers of Cu-Aβ40 complexes from 1-ms MD simulations (Table S7). (PDF 1092 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mantri, Y., Fioroni, M. & Baik, MH. Computational study of the binding of CuII to Alzheimer’s amyloid-β peptide: Do Aβ42 and Aβ40 bind copper in identical fashion?. J Biol Inorg Chem 13, 1197–1204 (2008). https://doi.org/10.1007/s00775-008-0403-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00775-008-0403-6

Keywords

Search

Navigation