Skip to main content

Advertisement

Springer Nature Link
Log in

Combining conformational sampling and selection to identify the binding mode of zinc-bound amyloid peptides with bifunctional molecules

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

The pathogenesis of Alzheimer’s disease (AD) has been suggested to be related with the aggregation of amyloid β (Aβ) peptides. Metal ions (e.g. Cu, Fe, and Zn) are supposed to induce the aggregation of Aβ. Recent development of bifunctional molecules that are capable of interacting with Aβ and chelating biometal ions provides promising therapeutics to AD. However, the molecular mechanism for how Aβ, metal ions, and bifunctional molecules interact with each other is still elusive. In this study, the binding mode of Zn2+-bound Aβ with bifunctional molecules was investigated by the combination of conformational sampling of full-length Aβ peptides using replica exchange molecular dynamics simulations (REMD) and conformational selection using molecular docking and classical MD simulations. We demonstrate that Zn2+-bound Aβ(1–40) and Aβ(1–42) exhibit different conformational ensemble. Both Aβ peptides can adopt various conformations to recognize typical bifunctional molecules with different binding affinities. The bifunctional molecules exhibit their dual functions by first preferentially interfering with hydrophobic residues 17–21 and/or 30–35 of Zn2+-bound Aβ. Additional interactions with residues surrounding Zn2+ could possibly disrupt interactions between Zn2+ and Aβ, which then facilitate these small molecules to chelate Zn2+. The binding free energy calculations further demonstrate that the association of Aβ with bifunctional molecules is driven by enthalpy. Our results provide a feasible approach to understand the recognition mechanism of disordered proteins with small molecules, which could be helpful to the design of novel AD drugs.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Abbreviations

AD:

Alzheimer’s disease

Aβ:

Amyloid-β

REMD:

Replica exchange molecular dynamics

HBX:

2-(2-Hydroxylphenyl)benzoxazole

MPY′:

4-(5-Hydoxylimidazo[1,2-a]pyridin-2-yl)-N,N-dimethylaniline

L2B:

N1,N1-dimethyl-N4-(pyridin-2-ylmethyl)benzene-1,4-diamine

EDTA:

Ethylenediaminetetraacetic acid

CQ:

Clioquinol, 5-chloro-7-iodo-8-hydroxyquinoline

PBT2:

8-Hydroxyquinoline derivative

References

  1. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

    Article  CAS  Google Scholar 

  2. Jakob-Roetne R, Jacobsen H (2009) Alzheimer’s disease: from pathology to therapeutic approaches. Angew Chem Int Ed 48:3030–3059

    Article  CAS  Google Scholar 

  3. Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10:698–712

    Article  CAS  Google Scholar 

  4. Straub JE, Thirumalai D (2011) Toward a molecular theory of early and late events in monomer to amyloid fibril formation. Ann Rev Phys Chem 62:437–463

    Article  CAS  Google Scholar 

  5. Perry G, Cash AD, Srinivas R, Smith MA (2002) Metals and oxidative homeostasis in Alzheimer’s disease. Drug Dev Res 56:293–299

    Article  CAS  Google Scholar 

  6. Bush AI (2003) The metallobiology of Alzheimer’s disease. Trends Neurosci 26:207–214

    Article  CAS  Google Scholar 

  7. Maynard CJ, Bush AI, Masters CL, Cappai R, Li QX (2005) Metals and amyloid-beta in Alzheimer’s disease. Int J Exp Pathol 86:147–159

    Article  CAS  Google Scholar 

  8. Shcherbatykh I, Carpenter DO (2007) The role of metals in the etiology of Alzheimer’s disease. J Alzheimers Dis 11:191–205

    CAS  Google Scholar 

  9. Bush AI, Tanzi RE (2008) Therapeutics for Alzheimer’s disease based on the metal hypothesis. Neurotherapeutics 5:421–432

    Article  CAS  Google Scholar 

  10. Chiang PK, Lam MA, Luo Y (2008) The many faces of amyloid β in Alzheimer’s disease. Curr Mol Med 8:580–584

    Article  CAS  Google Scholar 

  11. Miura T, Suzuki K, Kohata N, Takeuchi H (2000) Metal binding modes of Alzheimer’s amyloid β-peptide in insoluble aggregates and soluble complexes. Biochemistry 39:7024–7031

    Article  CAS  Google Scholar 

  12. Kozin SA, Zirah S, Rebuffat S, Hoa GH, Debey P (2001) Zinc binding to Alzheimer’s Aβ(1–16) peptide results in stable soluble complex. Biochem Biophys Res Commun 285:959–964

    Article  CAS  Google Scholar 

  13. Minicozzi V, Stellato F, Comai M, Dalla Serra M, Potrich C, Meyer-Klaucke W, Morante S (2008) Identifying the minimal copper- and zinc-binding site sequence in amyloid-β peptides. J Biol Chem 283:10784–10792

    Article  CAS  Google Scholar 

  14. Faller P, Hureau C (2009) Bioinorganic chemistry of copper and zinc ions coordinated to amyloid-β peptide. Dalton Trans 21:1080–1094

    Article  Google Scholar 

  15. Faller P (2009) Copper and zinc binding to amyloid-β: coordination dynamics aggregation reactivity and metal-ion transfer. ChemBioChem 10:2837–2845

    Article  CAS  Google Scholar 

  16. Tõugu V, Tiiman A, Palumaa P (2011) Interactions of Zn(II) and Cu(II) ions with Alzheimer’s amyloid-β peptide Metal ion binding contribution to fibrillization and toxicity. Metallomics 3:250–261

    Article  Google Scholar 

  17. Watt NT, Whitehouse IJ, Hooper NM (2011) The role of zinc in Alzheimer’s disease. Int J Alzheimers Dis 2011:971021–971030

    Google Scholar 

  18. Rezaei-Ghaleh N, Giller K, Becker S, Zweckstetter M (2011) Effect of zinc binding on β-amyloid structure and dynamics: implications for Aβ aggregation. Biophys J 101:1202–1211

    Article  CAS  Google Scholar 

  19. Zirah S, Kozin SA, Mazur AK, Blond A, Cheminant M, Ségalas-Milazzo I, Debey P, Rebuffat S (2006) Structural changes of region 1–16 of the Alzheimer disease amyloid β-peptide upon zinc binding and in vitro aging. J Biol Chem 281:2151–2161

    Article  CAS  Google Scholar 

  20. Tsvetkov PO, Kulikova AA, Golovin AV, Tkachev YV, Archakov AI, Kozin SA, Makarov AA (2010) Minimal Zn2+ binding site of amyloid-β. Biophys J 99:L84–L86

    Article  CAS  Google Scholar 

  21. Mekmouche Y, Coppel Y, Hochgräfe K, Guilloreau L, Tallmard C, Mazarguil H, Faller P (2005) Characterization of the ZnII binding to the peptide amyloid-β1–16 linked to Alzheimer’s disease. ChemBioChem 6:1663–1671

    Article  CAS  Google Scholar 

  22. Gaggelli E, Janicka-Klos A, Jankowska E, Kozlowski H, Migliorini C, Molteni E, Valensin D, Valensin G, Wieczerzak E (2008) NMR studies of the Zn2 + interactions with rat and human β-amyloid (1–28) peptides in water-micelle environment. J Phys Chem B 112:100–109

    Article  CAS  Google Scholar 

  23. Furlan S, La Penna G (2009) Modeling of the Zn2 + binding in the 1–16 region of the amyloid β peptide involved in Alzheimer’s disease. Phys Chem Chem Phys 11:6468–6481

    Article  CAS  Google Scholar 

  24. Karr JW, Kaupp LJ, Szalai VA (2004) Amyloid-β binds Cu2+ in a mononuclear metal ion binding site. J Am Chem Soc 126:13534–13538

    Article  CAS  Google Scholar 

  25. Kowalik-Jankowska T, Ruta M, Wisniewska K, Lankiewicz L (2003) Coordination abilities of the 1–16 and 1–28 fragments of β-amyloid peptide towards copper(II) ions: a combined potentiometric and spectroscopic study. J Inorg Biochem 95:270–282

    Article  CAS  Google Scholar 

  26. Ma QF, Hu J, Wu WH, Liu HD, Du JT, Fu Y, Wu YW, Lei P, Zhao YF, Li YM (2006) Characterization of copper binding to the peptide amyloid-β(1–16) associated with Alzheimer’s disease. Biopolymers 83:20–31

    Article  CAS  Google Scholar 

  27. Baruch-Suchodolsky R, Fischer B (2008) Soluble amyloid β1–28-copper(I)/copper(II)/iron(II) complexes are potent antioxidants in cell-free systems. Biochemistry 47:7796–7806

    Article  CAS  Google Scholar 

  28. Gaggelli E, Grzonka Z, Kozlowski H, Migliorini C, Molteni E, Valensin D, Valensin G (2008) Structural features of the Cu(II) complex with the rat Aβ(1-28) fragment. Chem Commnu 341–343

  29. Shin BK, Saxena S (2008) Direct evidence that all three histidine residues coordinate to Cu(II) in amyloid-β1–16. Biochemistry 47:9117–9123

    Article  CAS  Google Scholar 

  30. Pedersen JT, Teilum K, Heegaard NHH, Østergaard J, Adolph HW, Hemmingsen L (2011) Rapid formation of a preoligomeric peptide-metal-peptide complex following copper(II) binding to Amyloid β peptides. Angew Chem Int Ed 50:2532–2535

    Article  CAS  Google Scholar 

  31. Miller Y, Ma B, Nussinov R (2010) Polymorphism in Alzheimer Aβ amyloid organization reflects conformational selection in a rugged energy landscape. Chem Rev 110:4820–4838

    Article  CAS  Google Scholar 

  32. Colletier JP, Laganowsky A, Landau M, Zhao M, Soriaga AB, Goldschmidt L, Flot D, Cascio D, Sawaya MR, Eisenberg D (2011) Molecular basis for amyloid-β polymorphism. Proc Natl Acad Sci USA 108:16938–16943

    Article  CAS  Google Scholar 

  33. Yu X, Zheng J (2011) Polymorphic structures of Alzheimer’s β-amyloid globulomers. PLoS One 6:e20575

    Article  CAS  Google Scholar 

  34. Miller Y, Ma B, Nussinov R (2010) Zinc ions promote Alzheimer Aβ aggregation via population shift of polymorphic states. Proc Natl Acad Sci USA 107:9490–9495

    Article  CAS  Google Scholar 

  35. Parthasarathy S, Long F, Miller Y, Xiao Y, McElheny D, Thurber K, Ma B, Nussinov R, Ishii Y (2011) Molecular-level examination of Cu2+ binding structure for amyloid fibrils of 40-residue Alzheimer’s β by solid-state NMR spectroscopy. J Am Chem Soc 133:3390–3400

    Article  CAS  Google Scholar 

  36. Ricchelli F, Drago D, Filippi B, Tognon G, Zatta P (2005) Aluminum-triggered structural modifications and aggregation of β-amyloids. Cell Mol Life Sci 62:1724–1733

    Article  CAS  Google Scholar 

  37. Miller Y, Ma B, Nussinov R (2012) Metal binding sites in amyloid oligomers: Complexes and mechanisms. Coord Chem Rev. doi:10.1016/j.ccr.2011.12.022

  38. Cohen T, Frydman-Marom A, Rechter M, Gazit E (2006) Inhibition of amyloid fibril formation and cytotoxicity by hydroxyindole derivatives. Biochemistry 45:4727–4735

    Article  CAS  Google Scholar 

  39. Yadav A, Sonker M (2009) Perspectives in designing anti aggregation agents as Alzheimer disease drugs. Eur J Med Chem 44:3866–3873

    Article  CAS  Google Scholar 

  40. Kim S, Chang WE, Kumar R, Klimov DK (2011) Naproxen interferes with the assembly of Aβ oligomers implicated in Alzheimer’s disease. Biophys J 100:2024–2032

    Article  CAS  Google Scholar 

  41. Schütz AK, Soragni A, Hornemann S, Aguzzi A, Ernst M, Böckmann A, Meier BH (2011) The amyloid-Congo red interface at atomic resolution. Angew Chem Int Ed 50:5956–5960

    Article  Google Scholar 

  42. Sood A, Abid M, Sauer C, Hailemichael S, Foster M, Török B, Török M (2011) Disassembly of preformed amyloid beta fibrils by small organofluorine molecules. Bioorg Med Chem Lett 21:2044–2047

    Article  CAS  Google Scholar 

  43. Shiri S, Michal L, Anat F, Yaniv A, Roni S, Ludmila B, Ehud G, Hanoch S (2011) Quantitative structure–activity relationship analysis of β-amyloid aggregation inhibitors. J Comput Aided Mol Des 25:135–144

    Article  Google Scholar 

  44. Viet MH, Ngo ST, Lam NS, Li MS (2011) Inhibition of aggregation of amyloid peptides by beta-sheet breaker peptides and their binding affinity. J Phys Chem B 115:7433–7446

    Article  CAS  Google Scholar 

  45. Urbanc B, Betnel M, Cruz L, Li H, Fradinger EA, Monien BH, Bitan G (2011) Structural basis for Aβ 1–42 toxicity inhibition by Aβ C-terminal fragments: discrete molecular dynamics study. J Mol Biol 410:316–328

    Article  CAS  Google Scholar 

  46. Yoo SI, Yang M, Brender JR, Subramanian V, Sun K, Joo NE, Jeong SH, Ramamoorthy A, Kotov NA (2011) Inhibition of amyloid peptide fibrillation by inorganic nanoparticles: functional similarities with proteins. Angew Chem Int Ed 50:5110–5115

    Article  CAS  Google Scholar 

  47. Finefrock AE, Bush AI, Doraiswamy PM (2003) Current status of metals as therapeutic targets in Alzheimer’s disease. J Am Geriatr Soc 51:1143–1148

    Article  Google Scholar 

  48. Bush AI (2008) Drug development based on the metals hypothesis of Alzheimer’s disease. J Alzheimers Dis 15:223–240

    CAS  Google Scholar 

  49. Hider RC, Ma YM, Molina-Holgado F, Gaeta A, Roy S (2008) Iron chelation as a potential therapy for neurodegenerative disease. Biochem Soc Trans 36:1304–1308

    Article  CAS  Google Scholar 

  50. Perez LR, Franz KJ (2010) Minding metals: tailoring multifunctional chelating agents for neurodegenerative disease. Dalton Trans 39:2177–2187

    Article  CAS  Google Scholar 

  51. Rodríguez-Rodríguez C, de Groot NS, Rimola A, Álvarez-Larena A, Lloveras V, Vidal-Gancedo J, Ventura S, Vendrell J, Sodupe M, González-Duarte P (2009) Design selection and characterization of thioflavin-based intercalation compounds with metal chelating properties for application in Alzheimer’s disease. J Am Chem Soc 131:1436–1451

    Article  Google Scholar 

  52. Mancino AM, Hindo SS, Kochi A, Lim MH (2009) Effects of clioquinol on metal-triggered amyloid-β aggregation revisited. Inorg Chem 48:9596–9598

    Article  CAS  Google Scholar 

  53. Braymer JJ, Detoma AS, Choi JS, Ko KS, Lim MH (2011) Recent development of bifunctional small molecules to study metal-amyloid-β species in Alzheimer’s disease. Int J Alzheimers Dis 2011:623051–623060

    Google Scholar 

  54. Hindo SS, Mancino AM, Braymer JJ, Liu Y, Vivekanandan S, Ramamoorthy A, Lim MH (2009) Small molecule modulators of copper-induced Abeta aggregation. J Am Chem Soc 131:16663–16665

    Article  CAS  Google Scholar 

  55. Choi JS, Braymer JJ, Nanga RPR, Ramamoorthy A, Lim MH (2010) Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity. Proc Natl Acad Sci USA 107:21990–21995

    Article  CAS  Google Scholar 

  56. Wu WH, Lei P, Liu Q, Hu J, Gunn AP, Chen MS, Rui YF, Su XY, Xie ZP, Zhao YF, Bush AI, Li YM (2008) Sequestration of copper from β-amyloid promotes selective lysis by cyclen-hybrid cleavage agents. J Biol Chem 283:31657–31664

    Article  CAS  Google Scholar 

  57. Jensen M, Canning A, Chiha S, Bouquerel P, Pedersen JT, Østergaard J, Cuvillier O, Sasaki I, Hureau C, Faller P (2012) Inhibition of Cu-amyloid-β by using bifunctional peptides with β-sheet breaker and chelator moieties. Chem Eur J 18:4836–4839

    Article  CAS  Google Scholar 

  58. Dedeoglu A, Cormier K, Payton S, Tseitlin KA, Kremsky JN, Lai L, Li XH, Moir RD, Tanzi RE, Bush AI, Kowall NW, Rogers JT, Huang XD (2004) Preliminary studies of a novel bifunctional metal chelator targeting Alzheimer’s amyloidogenesis. Expl Gerontol 39:1641–1649

    Article  CAS  Google Scholar 

  59. Boehr DD, Nussinov R, Wright PE (2009) The role of dynamic conformational ensembles in biomolecular recognition. Nat Chem Biol 5:789–796

    Article  CAS  Google Scholar 

  60. Sugita Y, Okamoto Y (1999) Replica-exchange molecular dynamics method for protein folding. Chem Phys Lett 314:141–151

    Article  CAS  Google Scholar 

  61. Mitsutake A, Sugita Y, Okamoto Y (2001) Generalized-ensemble algorithms for molecular simulations of biopolymers. Biopolymers 60:96–123

    Article  CAS  Google Scholar 

  62. 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 

  63. Huey R, Morris GM, Olson AJ, Goodsell DS (2007) A semiempirical free energy force field with charge-based desolvation. J Comput Chem 28:1145–1152

    Article  CAS  Google Scholar 

  64. Kollman PA, Massova I, Reyes C, Kuhn B, Huo SH, Chong L, Lee M, Lee T, Duan Y, Wang W, Donini O, Cieplak P, Srinivasan J, Case DA, Cheatham TE (2000) Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Acc Chem Res 33:889–897

    Article  CAS  Google Scholar 

  65. Hoops SC, Anderson KW, Merz KM (1991) Force-field design for metalloproteins. J Am Chem Soc 113:8262–8270

    Article  CAS  Google Scholar 

  66. Peters MB, Yang Y, Wang B, Füsti-Molnár L, Weaver MN, Merz KM Jr (2010) Structural survey of zinc containing proteins and the development of the zinc AMBER force field (ZAFF). J Chem Theory Comput 6:2935–2947

    Article  CAS  Google Scholar 

  67. Lin F, Wang RX (2010) Systematic derivation of AMBER force field parameters applicable to zinc-containing systems. J Chem Theory Comput 6:1852–1870

    Article  CAS  Google Scholar 

  68. Wang JM, Cieplak P, Kollman PA (2000) How well does a restrained electrostatic potential (RESP) model perform in calculating conformational energies of organic and biological molecules? J Comput Chem 21:1049–1074

    Article  CAS  Google Scholar 

  69. Lührs T, Ritter C, Adrian M, Riek-Loher D, Bohrmann B, Döeli 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  Google Scholar 

  70. Li WF, Zhang J, Su Y, Wang J, Qin M, Wang W (2007) Effects of zinc binding on the conformational distribution of the amyloid-β peptide based on molecular dynamics simulations. J Phys Chem B 111:13814–13821

    Article  CAS  Google Scholar 

  71. Miller Y, Ma BY, Nussinov R (2011) The unique Alzheimer’s β-amyloid triangular fibril has a cavity along the fibril axis under physiological conditions. J Am Chem Soc 133:2742–2748

    Article  CAS  Google Scholar 

  72. Yang MF, Teplow DB (2008) Amyloid β-protein monomer folding: free-energy surfaces reveal alloform-specific differences. J Mol Biol 384:450–464

    Article  CAS  Google Scholar 

  73. Sgourakis NG, Merced-Serrano M, Boutsidis C, Drineas P, Du ZM, Wang CY, Garcia AE (2011) Atomic-level characterization of the ensemble of the Aβ(1–42) Monomer in water using unbiased molecular dynamics simulations and spectral algorithms. J Mol Biol 405:570–583

    Article  CAS  Google Scholar 

  74. Sgourakis NG, Yan YL, McCallum SA, Wang CY, Garcia AE (2007) The Alzheimer’s peptides Aβ 40 and 42 adopt distinct conformations in water: a combined MD/NMR study. J Mol Biol 368:1448–1457

    Article  CAS  Google Scholar 

  75. Jang S, Shin S (2006) Amyloid β-peptide oligomerization in silico: dimer and trimer. J Phys Chem B 110:1955–1958

    Article  CAS  Google Scholar 

  76. Case DA, Darden TA, Cheatham III TE, Simmerling CL, Wang J, Duke RE, Luo R, Walker RC, Zhang W, Merz KM, Roberts BP, Wang B, Hayik S, Roitberg A, Seabra G, Kolossvai I, Wong KF, Paesani F, Vanicek J, Liu J, Wu X, Brozell SR, Steinbrecher T, Gohlke H, Cai Q, Ye X, Wang J, Hsieh MJ, Cui G, Roe DR, Mathews DH, Seetin MG, Sagui C, Babin V, Luchko T, Gusarov S, Kovalenko A, Kollman PA (2010) AMBER 11; University of California San Francisco

  77. Hornak V, Abel R, Okur A, Strockbine B, Roitberg A, Simmerling C (2006) Comparison of multiple amber force fields and development of improved protein backbone parameters. Proteins 65:712–725

    Article  CAS  Google Scholar 

  78. Onufriev A, Bashford D, Case DA (2004) Exploring protein native states and large-scale conformational changes with a modified generalized born model. Proteins 55:383–394

    Article  CAS  Google Scholar 

  79. Daura X, Gademann K, Jaun B, Seebach D, van Gunsteren WF, Mark AE (1999) Peptide folding: when simulation meets experiment. Angew Chem Int Ed 38:236–240

    Article  CAS  Google Scholar 

  80. Wang JM, Wang W, Kollman PA, Case DA (2006) Automatic atom type and bond type perception in molecular mechanical calculations. J Mol Graph Model 25:247–260

    Article  Google Scholar 

  81. Wang JM, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) Development and testing of a general amber force field. J Comput Chem 25:1157–1174

    Article  CAS  Google Scholar 

  82. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926–935

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  85. Khandogin J, Brooks CL (2007) Linking folding with aggregation in Alzheimer’s β-amyloid peptides. Proc Natl Acad Sci USA 104:16880–16885

    Article  CAS  Google Scholar 

  86. Yan YL, Wang CY (2006) Aβ 42 is more rigid than Aβ 40 at the C terminus: implications for Aβ aggregation and toxicity. J Mol Biol 364:853–862

    Article  CAS  Google Scholar 

  87. Hou LM, Shao HY, Zhang YB, Li H, Menon NK, Neuhaus EB, Brewer JM, Byeon IJL, Ray DG, Vitek MP, Iwashita T, Makula RA, Przybyla AB, Zagorski MG (2004) Solution NMR studies of the Aβ(1–40) and Aβ(1–42) peptides establish that the met35 oxidation state affects the mechanism of amyloid formation. J Am Chem Soc 126:1992–2005

    Article  CAS  Google Scholar 

  88. Liu RT, McAllister C, Lyubchenko Y, Sierks MR (2004) Residues 17–20 and 30–35 of beta-amyloid play critical roles in aggregation. J Neurosci Res 75:162–171

    Article  CAS  Google Scholar 

  89. Baumketner A, Shea JE (2007) The structure of the Alzheimer amyloid β 10–35 peptide probed through replica-exchange molecular dynamics simulations in explicit solvent. J Mol Biol 366:275–285

    Article  CAS  Google Scholar 

  90. Riek R, Güntert P, Döbeli H, Wipf B, Wüthrich K (2001) NMR studies in aqueous solution fail to identify significant conformational differences between the monomeric forms of two Alzheimer peptides with widely different plaque-competence Aβ(1–40)ox and Aβ(1–42)ox. Eur J Biochem 268:5930–5936

    Article  CAS  Google Scholar 

  91. Yu L, Edalji R, Harlan JE, Holzman TF, Lopez AP, Labkovsky B, Hillen H, Barghorn S, Ebert U, Richardson PL, Miesbauer L, Solomon L, Bartley D, Walter K, Johnson RW, Hajduk PJ, Olejniczak ET (2009) Structural characterization of a soluble amyloid β-peptide oligomer. Biochemistry 48:1870–1877

    Article  CAS  Google Scholar 

  92. Bitan G, Kirkitadze MD, Lomakin A, Vollers SS, Benedek GB, Teplow DB (2003) Amyloid β-protein (Aβ) assembly: Aβ40 and Aβ42 oligomerize through distinct pathways. Proc Natl Acad Sci USA 100:330–335

    Article  CAS  Google Scholar 

  93. Schmidt M, Sachse C, Richter W, Xu C, Fandrich M, Grigorieff N (2009) Comparison of Alzheimer Aβ(1–40) and Aβ(1–42) amyloid fibrils reveals similar protofilament structures. Proc Natl Acad Sci USA 106:19813–19818

    CAS  Google Scholar 

  94. Sánchez L, Madurga S, Pukala T, Vilaseca M, López-Iglesias C, Robinson CV, Giralt E, Carulla N (2011) Aβ40 and Aβ42 amyloid fibrils exhibit distinct molecular recycling properties. J Am Chem Soc 133:6505–6508

    Article  Google Scholar 

  95. Alonso H, Bliznyuk AA, Gready JE (2006) Combining docking and molecular dynamic simulations in drug design. Med Res Rev 26:531–568

    Article  CAS  Google Scholar 

  96. Li J, Liu R, Lam KS, Jin LW, Duan Y (2011) Alzheimer’s disease drug candidates stabilize A-β protein native structure by interacting with the hydrophobic core. Biophys J 100:1076–1082

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to Dr. Orkid Coskuner-Weber (The University of Texas at San Antonio, USA) for critical comments of this research. Computations were performed on the clusters at the High-Performance Computing Center of Dalian University of Technology. This work is supported by the Major State Basic Research Development Program (Grant No. 200900376). Dr. Xu and Dr. Bao thanks financial support from the Fundamental Research Funds for the Central Universities (grant No. DUT12LK38 and DUT11SM01).

Author information

Authors and Affiliations

  1. School of Chemistry, Dalian University of Technology, Dalian, 116024, China

    Liang Xu, Ke Gao & Chunyu Bao

  2. Department of Engineering Mechanics, State Key Laboratory of Structural Analyses for Industrial Equipment, Dalian University of Technology, Dalian, 116023, China

    Xicheng Wang

Authors
  1. Liang Xu
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Ke Gao
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Chunyu Bao
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Xicheng Wang
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Liang Xu.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10822_2012_9588_MOESM1_ESM.doc

Supplementary Material The computational details of RESP charges for the model structures, as well as figures mentioned in the main text are provided in the Supplementary Material. (DOC 10712 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xu, L., Gao, K., Bao, C. et al. Combining conformational sampling and selection to identify the binding mode of zinc-bound amyloid peptides with bifunctional molecules. J Comput Aided Mol Des 26, 963–976 (2012). https://doi.org/10.1007/s10822-012-9588-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-012-9588-4

Keywords