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Exploration of the mechanism for LPFFD inhibiting the formation of β-sheet conformation of Aβ(1–42) in water

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Abstract

The main component of senile plaques found in AD brain is amyloid β-peptide (Aβ), and the neurotoxicity and aggregation of Aβ are associated with the formation of β-sheet structure. Experimentally, beta sheet breaker (BSB) peptide fragment Leu-Pro-Phe-Phe-Asp (LPFFD) can combine with Aβ, which can inhibit the aggregation of Aβ. In order to explore why LPFFD can inhibit the formation of β-sheet conformation of Aβ at atomic level, first, molecular docking is performed to obtain the binding sites of LPFFD on the Aβ(1–42) (LPFFD/Aβ(1–42)), which is taken as the initial conformation for MD simulations. Then, MD simulations on LPFFD/Aβ(1–42) in water are carried out. The results demonstrate that LPFFD can inhibit the conformational transition from α-helix to β-sheet structure for the C-terminus of Aβ(1–42), which may be attributed to the hydrophobicity decreasing of C-terminus residues of Aβ(1–42) and formation probability decreasing of the salt bridge Asp23-Lys28 in the presence of LPFFD.

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References

  1. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Muller-Hill B (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325:733–736

    Article  CAS  Google Scholar 

  2. Chromy BA, Nowak RJ, Lambert MP, Viola KL, Chang L, Velasco PT, Jone’s BW, Fernandez SJ, Laco’r PN, Horowitz P, Finch CE, Krafft GA, Klein WL (2003) Self-assembly of Aβ into globular neurotoxins. Biochemistry 42:12749–12760

    Article  CAS  Google Scholar 

  3. Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–185

    Article  CAS  Google Scholar 

  4. Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y (1994) Visualization of Aβ42(43) and Aβ40 in senile plaques with end-specific Aβ monoclonals: evidence that an initially deposited species is Aβ42(43). Neuron 13:45–53

    Article  CAS  Google Scholar 

  5. Gravina SA, Ho L, Eckman CB, Long KE, Otvos L, Younkin LH, Suzuki N, Younkin SG (1995) Amyloid β protein (Aβ) in Alzheimer’s disease brain. J Biol Chem 270:7013–7016

    Article  CAS  Google Scholar 

  6. Golde TE, Eckman CB, Younkin SG (2000) Biochemical treatment of Alzheimer’s disease. Biochim Biophys Acta 1502:172–187

    CAS  Google Scholar 

  7. Barrow CJ, Zagorski MG (1991) Solution structure of β peptide and its constituent fragments: relation to amyloid deposition. Science 253:179–181

    Article  CAS  Google Scholar 

  8. Barrow CJ, Yasuda A, Kenny PTM, Zagorski MG (1992) Solution conformations and aggregational properties of synthetic amyloid β-peptides of Alzheimer’s disease. J Mol Biol 225:1075–1093

    Article  CAS  Google Scholar 

  9. Hilbich C, Kisters-Woide B, Reed J, Masters CL, Beyreuther K (1991) Aggregation and secondary structure of synthetic amyloid βA4 peptides of Alzheimer;s disease. J Mol Biol 218:149–163

    Article  CAS  Google Scholar 

  10. Kirchner DA, Inouye H, Duffy LK, Sinclair A, Lind M, Selkoe D (1987) Synthetic peptide homologous to beta protein from Alzheimer disease forms amyloid-like fibrils in vitro. Proc Natl Acad Sci USA 84:6953–6957

    Article  Google Scholar 

  11. Gorevic PD, Castano EM, Sarma R, Frangione B (1987) Ten to fourteen residue peptides of Alzheimer’s disease protein are sufficient for amyloid fibril formation and its characteristic x-ray diffraction pattern. Biochem Biophys Res Commun 147:854–862

    Article  CAS  Google Scholar 

  12. Shen CL, Murphy RM (1995) Solvent effects on self-assembly of β-amyloid peptide. Biophys J 69:640–651

    Article  CAS  Google Scholar 

  13. Behl C, Davis JB, Lesley R, Schubert D (1994) Hydrogen peroxide mediates amyloid β protein toxicity. Cell 77:817–827

    Article  CAS  Google Scholar 

  14. Harris ME, Hensley K, Butterfield DA, Leedle RA, Carney JM (1995) Direct evidence of oxidative injure produced by the Alzheimer’s β-amyloid peptide (1–40) in culture hippocampal neurons. Exp Neurol 131:193–202

    Article  CAS  Google Scholar 

  15. Buchet R, Tavitian E, Ristig D, Swoboda R, Stauss U, Gremlich HU, Fourniere LL, Staufenbiel M, Frey P, Lowe DA (1996) Conformations of synthetic β peptides in solid state and in aqueous solution: relation to toxicity in PC12 cells. Biochim Biophys Acta 1315:40–46

    Google Scholar 

  16. Simmons LK, May PC, Tomaselli KJ, Rydel RE, Fuson KS, Brigham EF, Wright S, Lieberburg I, Becker GW, Brems DN (1994) Secondary structure of amyloid beta peptide correlates with neurotoxic activity in vitro. Mol Pharmacol 45:373–379

    CAS  Google Scholar 

  17. Greenfield NJ, Fasman GD (1969) Computed circular dichroism spectra for the evaluation of protein conformation. Biochemistry 8:4108–4116

    Article  CAS  Google Scholar 

  18. Tomski S, Murphy RM (1992) Kinetics of aggregation of synthetic β-amyloid peptide. Arch Biochem Biophys 294:630–638

    Article  CAS  Google Scholar 

  19. Walencewicz-Wasserman AJ, Kosmoski J, Cribbs DH, Glabe CG, Cotman CW (1995) Structure-activity analyses of β-peptides: conformations of the β25–35 region to aggregation and neurotoxicity. J Neurochem 64:253–265

    Google Scholar 

  20. Lorenzo A, Yankner BA (1994) Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc Natl Acad Sci USA 91:12243–12447

    Article  CAS  Google Scholar 

  21. Soto C, Castano EM, Kumar RA, Beavis R, Frangione CB (1995) Fibrillogenesis of synthetic amyloid-β peptides is dependent on their initial secondary structure. Neurosci Lett 200:105–108

    Article  CAS  Google Scholar 

  22. Jarrett JT, Berger EP Jr, Lansbury PT (1993) The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry 32:4693–4697

    Article  CAS  Google Scholar 

  23. Snyder SW, Ladror US, Wade WS, Wang GT, Barrett LW, Matayoshi ED (1994) Amyloid-β aggregation: selective inhibition of aggregation in mixtures of amyloid with different chain lengths. Biophys J 67:1216–1228

    Article  CAS  Google Scholar 

  24. Soto C, Castano EM (1996) The conformation of Alzheimer’s β peptide determines the rate of amyloid formation and its resistance to proteolysis. Biochem J 314:701–707

    CAS  Google Scholar 

  25. Salomon AR, Marcinowski KJ, Friedland RP, Zagorski MG (1996) Nicotine inhibits amyloid formation by the β-peptide. Biochemistry 35:13568–13578

    Article  CAS  Google Scholar 

  26. Moore SA, Huckerby TN, Gibson GL, Fullwood NJ, Turnbull S, Tabner BJ, El-Agnaf OM, Allsop D (2004) Both the D-(+) and L-(-) enantiomers of nicotine inhibit Aβ aggregation and cytotoxicity. Biochemistry 43:819–826

    Article  CAS  Google Scholar 

  27. Wood SJ, MacKenzie L, Maleef B, Hurle MR, Wetzel R (1996) Selective inhibition of Aβ fibril formation. J Biol Chem 271:4086–4092

    Article  CAS  Google Scholar 

  28. Merlini G, Ascari E, Amboldi N, Belloti V, Arbustini E, Perfetti V, Ferrari M, Zorzoli I, Marinone MG, Garini P, Diegoli M (1995) Interaction of the anthracycline 4′-iodo-4′-deoxyd- oxorubic with amyloid fibrils: inhibition of amyloidogenesis. Proc Natl Acad Sci USA 92:2959–2963

    Article  CAS  Google Scholar 

  29. Wang SS, Chen YT, Chou SW (2005) Inhibition of amyloid fibril formation of β-amyloid peptides via the amphiphilic surfactants. Biochim Biophys Acta 1741:307–313

    CAS  Google Scholar 

  30. Tjernberg LO, Näslund J, Lindqvist F, Johansson J, Karlström AR, Thyberg J, Terenius L, Nordstedt C (1996) Arrest of β-amyloid fibril formation by a pentapeptide ligand. J Biol Chem 271:8545–8548

    Article  CAS  Google Scholar 

  31. Soto C, Sogurdsson EM, Morello L, Kumar RA, Castano EM, Frangione B (1998) Β-sheet breaker peptides inhibit fibtillogenesis in a rat brain model of amyloidosis: implications for Alzheimer’s therapy. Nat Med 4:822–826

    Article  CAS  Google Scholar 

  32. Soto C, Saborio GP, Permanne B (2000) Inhibit the conversion of soluble amyloid-beta peptide into abnormally folded amyloidogenic intermediates: relevance for Alzheimer’s disease therapy. Acta Neurol Scand Suppl 176:90–95

    Article  CAS  Google Scholar 

  33. Andrew JD (2007) Peptide inhibitors of β-amyloid aggregation. Curr Opin Drug Discov Devel 10:533–539

    Google Scholar 

  34. Hetényi C, Kortvelyesi T, Penke B (2001) Computational studies on the binding of β-sheet breaker (BSB) peptides on amyloid βA(1–42). THEOCHEM 542:25–31

    Article  Google Scholar 

  35. Crescenzi O, Tomaselli S, Guerrini R, Salvadori S, D’Ursi AM, Temussi PA, Picone D (2002) Solution structure of the Alzheimer amyloid β-peptide (1–42) in an apolar microenvironment. Eur J Biochem 269:5642–5648

    Article  CAS  Google Scholar 

  36. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19:1639–1662

    Article  CAS  Google Scholar 

  37. Berendsen HJC, van der Spoel D, van Drunen R (1995) GROMACS: a message-passing parallel molecular dynamics implementation. Comput Phys Commun 91:43–56

    Article  CAS  Google Scholar 

  38. Lindahl E, Hess B, van der Spoel D (2001) GROMACS 3.0: a package for molecular simulations and trajectory analysis. J Mol Model 7:306–317

    CAS  Google Scholar 

  39. Daura X, Mark AE, van Gunsteren WF (1998) Parameterization of aliphatic CHn united atoms of GROMOS96 force field. J Comput Chem 19:535–547

    Article  CAS  Google Scholar 

  40. Schuttelkopf AW, van-Aalten DMF (2004) PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr D 60:1355–1363

    Article  Google Scholar 

  41. Hess B, Bekker H, Berendsen HJC, Fraaije JGEM (1997) LINCS: a linear constraint solver for molecular simulation. J Comput Chem 18:1463–1472

    Article  CAS  Google Scholar 

  42. Berendsen HJC, Postma JPM, van Gunsteren WF, Dinola A, Haak JR (1984) Molecular dynamics with coupling to an external bath. J Chem Phys 81:3684–3690

    Article  CAS  Google Scholar 

  43. Darden T, York D, Pedersen L (1993) Particle mesh ewald: an N.log(N) method for ewald sums in large systems. J Chem Phys 98:10089–10092

    Article  CAS  Google Scholar 

  44. Patra M, Karttunen M, Hyvonen MT, Falck E, Lindqvist P, Vattulainen I (2003) Molecular dynamics simulations of lipid bilayers: major artifacts due to truncating electrostatic interaction. Biophys J 84:3636–3645

    Article  CAS  Google Scholar 

  45. Kabsch W, Sander C (1983) Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 22:2577–2637

    Article  CAS  Google Scholar 

  46. Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graphics 14:33–38

    Article  CAS  Google Scholar 

  47. Yang C, Li JY, Li Y, Zhu XL (2009) The effect of solvents on the conformations of Amyloid β-peptide (1–42) studied by molecular dynamics simulation. THEOCHEM 895:1–8

    Article  CAS  Google Scholar 

  48. Tjernberg LO, Tjernberg A, Bark N, Shi Y, Ruzsicska BP, Bu Z, Thyberg J, Callaway DJE (2002) Assembling amyloid fibrils from designed structures containing a significant amyloid β-peptide fragment. Biochem J 366:343–351

    CAS  Google Scholar 

  49. Torok M, Milton S, Kayed R, Wu P, McIntire T, Glabe CG, Langen R (2002) Structure and dynamics features of Alzheimer’s Aβ peptide in amyloid fibrils studied by site-directed spin labelling. J Biol Chem 277:40810–40815

    Article  Google Scholar 

  50. Balbach JJ, Petkova AT, Oyler NA, Antzutkin ON, Gordon DJ, Meredith SC, Tycko R (2002) Supramolecular structure in full-length Alzheimer’s β-amyloid fibrils: evidence for a parallel β-sheet organization from solid-state nuclear magnetic resonance. Biophys J 83:1205–1216

    Article  CAS  Google Scholar 

  51. Shen L, Ji HF, Zhang HY (2008) Why is the C-terminus of Aβ(1–42) more unfolded than that of Aβ(1–40)? Clue from hydrophobic interaction. J Phys Chem B 112:3164–3167

    Article  CAS  Google Scholar 

  52. Tarus B, Straub JE, Thirumalai DJ (2006) Dynamics of Asp23-Lys28 salt-bridge formation in Aβ10–35 monomers. J Am Chem Soc 128:16159–16168

    Article  CAS  Google Scholar 

  53. Lazo ND, Grant MA, Condron MC, Rigby AC, Teplow DB (2005) On the nucleation of amyloid β-protein monomer folding. Protein Sci 14:1581–1596

    Article  CAS  Google Scholar 

  54. Sciarretta KL, Gordon DJ, Petkova AT, Tycko R, Meredith SC (2005) Aβ40-lactam(D23/K28) models a conformation highly favorable for nucleation of amyloid. Biochemistry 44:6003–6014

    Article  CAS  Google Scholar 

  55. Luhrs T, Ritter C, Adrian M, Riek-Loher D, Bohrmann B, Dobeli H, Schubert D, Riek R (2005) 3D structure of Alzheimer’s amyloid-β(1–42) fibrils. Proc Natl Acad Sci USA 102:17342–17347

    Article  CAS  Google Scholar 

  56. Knecht V, Mhwald H, Lipowsky R (2007) Conformational diversity of the fibrillogenic fusion peptide B18 in different environments from molecular dynamics simulations. J Phys Chem B 111:4161–4170

    Article  CAS  Google Scholar 

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Acknowledgments

This work is supported by grants from the National Science Foundation of China (No. 20706029, 20876073), Jiangsu Science and Technology Department of China (BK2008372), and Nanjing University of Technology of China (No. ZK200803).

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  1. State Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemistry and Chemical Engineering, Nanjing University of Technology, Nanjing, 210009, China

    Cao Yang, Xiaolei Zhu, Jinyu Li & Rongwei Shi

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  1. Cao Yang
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  2. Xiaolei Zhu
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Correspondence to Xiaolei Zhu.

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Yang, C., Zhu, X., Li, J. et al. Exploration of the mechanism for LPFFD inhibiting the formation of β-sheet conformation of Aβ(1–42) in water. J Mol Model 16, 813–821 (2010). https://doi.org/10.1007/s00894-009-0594-y

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