Skip to main content
SpringerLink
Log in

Molecular Dynamics Studies on Amyloidogenic Proteins

  • Chapter
Computational Methods to Study the Structure and Dynamics of Biomolecules and Biomolecular Processes

Part of the book series: Springer Series in Bio-/Neuroinformatics ((SSBN,volume 1))

Abstract

Molecular dynamics simulations, coupled with experimental investigations, could improve our understanding of the protein aggregation and fibrillization process of amyloidogenic proteins. Computational tools are being applied to solve the protein aggregation and fibrillization problem, providing insight into amyloid structures and aggregation mechanisms. Experimental studies of the nature of protein aggregation are unfortunately limited by the structure of aggregates and their insolubility in water. The difficulties have stimulated the development of new experimental methods, and intensive efforts to match computational results with the results of experimental investigations. The number of papers published on simulations of amyloidogenic proteins has increased rapidly during the last decade. The simulation systems covered a range from simple peptides (Alzheimer Aβ peptides or peptides being fragments of amyloidogenic proteins), to large proteins (transthyretin, prion protein, cystatin C, β2-microglobulin etc.). In studies of aggregation, very important is the integration of experimental and computational methods. Computational simulations constitute an “analytical tool” for obtaining and processing biological information and to make useful explanations of the physicochemical principles of amyloidogenesis, as well as to understand the role of amino acid sequences in amyloidogenic proteins. Very efficient theoretical models for prediction of protein aggregation propensities from primary structures have been proposed. At a minimal computational cost, some of these models can determine putative, aggregationprone regions (“hot-spots”) within a protein sequence. The in silico simulations increase our understanding of the protein aggregation process. In this chapter, the molecular studies of amyloidogenic proteins like prion protein, transthyretin, and human cystatin C are presented. The MD studies of these proteins show the first steps during amyloids formation. In addition, in this chapter, the MD studies of protein fibrils are presented. Based on MD simulations of fibril models it is possible to interpret some experimental results and suggest a mechanism of elongation for the fibril protofilament formation.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Virchow, R.: Ueber eine im Gehirn und Rückenmark des Menschen aufgefundene Substanz mit der chemischen Reaction der Cellulose. Acad. Sci. (Paris) 37, 860–861 (1854)

    Google Scholar 

  2. Gertz, M.A., Lacy, M.Q., Dispenzieri, A., Hayman, S.R.: Amyloidosis. Best Pract. Res. Clin. Haematol. 18, 709–727 (2005)

    Google Scholar 

  3. Hawkins, P.N.: Diagnosis and treatment of amyloidosis. Ann. Rheum. Dis. 56, 631–633 (1997)

    Google Scholar 

  4. Stryer, L., Berg, J.M.: Biochemistry 5e + Hemoglobin Chapter for Biochem 6e. W H Freeman & Company (2005)

    Google Scholar 

  5. Reixach, N., Deechongkit, S., Jiang, X., Kelly, J.W., Buxbaum, J.N.: Tissue damage in the amyloidoses: Transthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue culture. Proc. Natl. Acad. Sci. USA 101, 2817–2822 (2004)

    Google Scholar 

  6. Harper, J.D., Wong, S.S., Lieber, C.M., Lansbury, P.T.: Observation of metastable Abeta amyloid protofibrils by atomic force microscopy. Chem. Biol. 4, 119–125 (1997)

    Google Scholar 

  7. Krebs, M.R.H., Macphee, C.E., Miller, A.F., Dunlop, I.E., Dobson, C.M., Donald, A.M.: The formation of spherulites by amyloid fibrils of bovine insulin. Proc. Natl. Acad. Sci. USA 101, 14420–14424 (2004)

    Google Scholar 

  8. Gosal, W.S., Morten, I.J., Hewitt, E.W., Smith, D.A., Thomson, N.H., Radford, S.E.: Competing pathways determine fibril morphology in the self-assembly of beta2-microglobulin into amyloid. J. Mol. Biol. 351, 850–864 (2005)

    Google Scholar 

  9. Ionescu-Zanetti, C., Khurana, R., Gillespie, J.R., Petrick, J.S., Trabachino, L.C., Minert, L.J., Carter, S.A., Fink, A.L.: Monitoring the assembly of Ig light-chain amyloid fibrils by atomic force microscopy. Proc. Natl. Acad. Sci. USA 96, 13175–13179 (1999)

    Google Scholar 

  10. Malisauskas, M., Zamotin, V., Jass, J., Noppe, W., Dobson, C.M., Morozova-Roche, L.A.: Amyloid protofilaments from the calcium-binding protein equine lysozyme: formation of ring and linear structures depends on pH and metal ion concentration. J. Mol. Biol. 330, 879–890 (2003)

    Google Scholar 

  11. Wahlbom, M., Wang, X., Lindström, V., Carlemalm, E., Jaskolski, M., Grubb, A.: Fibrillogenic oligomers of human cystatin C are formed by propagated domain swapping. J. Biol. Chem. 282, 18318–18326 (2007)

    Google Scholar 

  12. Kayed, R., Head, E., Thompson, J.L., McIntire, T.M., Milton, S.C., Cotman, C.W., Glabe, C.G.: Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300, 486–489 (2003)

    Google Scholar 

  13. Rousseau, F., Wilkinson, H., Villanueva, J., Serrano, L., Schymkowitz, J.W.H., Itzhaki, L.S.: Domain swapping in p13suc1 results in formation of native-like, cytotoxic aggregates. J. Mol. Biol. 363, 496–505 (2006)

    Google Scholar 

  14. Xu, S.: Aggregation drives “misfolding” in protein amyloid fiber formation. Amyloid. 14, 119–131 (2007)

    Google Scholar 

  15. Nguyen, H.D., Hall, C.K.: Spontaneous fibril formation by polyalanines; discontinuous molecular dynamics simulations. J. Am. Chem. Soc. 128, 1890–1901 (2006)

    Google Scholar 

  16. Buchete, N.-V., Tycko, R., Hummer, G.: Molecular Dynamics Simulations of Alzheimer’s β-Amyloid Protofilaments. J. Mol. Biol. 353, 804–821 (2005)

    Google Scholar 

  17. Haspel, N., Zanuy, D., Ma, B., Wolfson, H., Nussinov, R.: A comparative study of amyloid fibril formation by residues 15-19 of the human calcitonin hormone: a single beta-sheet model with a small hydrophobic core. J. Mol. Biol. 345, 1213–1227 (2005)

    Google Scholar 

  18. Röhrig, U.F., Laio, A., Tantalo, N., Parrinello, M., Petronzio, R.: Stability and structure of oligomers of the Alzheimer peptide Abeta16-22: from the dimer to the 32-mer. Biophys. J. 91, 3217–3229 (2006)

    Google Scholar 

  19. Deng, N.-J., Yan, L., Singh, D., Cieplak, P.: Molecular Basis for the Cu2+ Binding-Induced Destabilization of β2-Microglobulin Revealed by Molecular Dynamics Simulation. Biophys. J. 90, 3865–3879 (2006)

    Google Scholar 

  20. Yang, M., Lei, M., Huo, S.: Why is Leu55→Pro55 transthyretin variant the most amyloidogenic: Insights from molecular dynamics simulations of transthyretin monomers. Protein Sci. 12, 1222–1231 (2003)

    Google Scholar 

  21. Park, S., Saven, J.G.: Simulation of pH-dependent edge strand rearrangement in human beta-2 microglobulin. Protein Sci. 15, 200–207 (2005)

    Google Scholar 

  22. Armen, R.S., Daggett, V.: Characterization of two distinct beta2-microglobulin unfolding intermediates that lead to amyloid fibrils of different morphology. Biochemistry 44, 16098–16107 (2005)

    Google Scholar 

  23. Santini, S., Derreumaux, P.: Helix H1 of the prion protein is rather stable against environmental perturbations: molecular dynamics of mutation and deletion variants of PrP(90-231). Cell Mol. Life Sci. 61, 951–960 (2004)

    Google Scholar 

  24. DeMarco, M.L., Daggett, V.: From conversion to aggregation: protofibril formation of the prion protein. Proc. Natl. Acad. Sci. USA 101, 2293–2298 (2004)

    Google Scholar 

  25. Rodziewicz-Motowidło, S., Wahlbom, M., Wang, X., Lagiewka, J., Janowski, R., Jaskolski, M., Grubb, A., Grzonka, Z.: Checking the conformational stability of cystatin C and its L68Q variant by molecular dynamics studies: why is the L68Q variant amyloidogenic? J. Struct. Biol. 154, 68–78 (2006)

    Google Scholar 

  26. DuBay, K.F.K., Pawar, A.P.A., Chiti, F.F., Zurdo, J.J., Dobson, C.M.C., Vendruscolo, M.M.: Prediction of the Absolute Aggregation Rates of Amyloidogenic Polypeptide Chains. J. Mol. Biol. 341, 10–10 (2004)

    Google Scholar 

  27. Fernandez-Escamilla, A.-M., Rousseau, F., Schymkowitz, J., Serrano, L.: Prediction of sequence-dependent and mutational effects on the aggregation of peptides and proteins. Nat. Biotechnol. 22, 1302–1306 (2004)

    Google Scholar 

  28. Tartaglia, G.G., Cavalli, A., Pellarin, R., Caflisch, A.: Prediction of aggregation rate and aggregation-prone segments in polypeptide sequences. Protein Sci. 14, 2723–2734 (2005)

    Google Scholar 

  29. Ma, B., Nussinov, R.: Simulations as analytical tools to understand protein aggregation and predict amyloid conformation. Curr. Opin. Chem. Biol. 10, 445–452 (2006)

    Google Scholar 

  30. Borreguero, J.M., Urbanc, B., Lazo, N.D., Buldyrev, S.V., Teplow, D.B., Stanley, H.E.: Folding events in the 21-30 region of amyloid beta-protein (Abeta) studied in silico. Proc. Natl. Acad. Sci. USA 102, 6015–6020 (2005)

    Google Scholar 

  31. Wei, G., Mousseau, N., Derreumaux, P.: Sampling the Self-Assembly Pathways of KFFE Hexamers. Biophys. J. 87, 3648–3656 (2004)

    Google Scholar 

  32. Baumketner, A., Shea, J.-E.: Free energy landscapes for amyloidogenic tetrapeptides dimerization. Biophys. J. 89, 1493–1503 (2005)

    Google Scholar 

  33. Han, W., Wu, Y.-D.: A strand-loop-strand structure is a possible intermediate in fibril elongation: long time simulations of amyloid-beta peptide (10-35). J. Am. Chem. Soc. 127, 15408–15416 (2005)

    Google Scholar 

  34. Ma, B., Nussinov, R.: Molecular dynamics simulations of the unfolding of 2-microglobulin and its variants. Protein Eng. Des. Sel. 16, 561–575 (2003)

    Google Scholar 

  35. Moraitakis, G., Goodfellow, J.M.: Simulations of Human Lysozyme: Probing the Conformations Triggering Amyloidosis. Biophys. J. 84, 2149–2158 (2003)

    Google Scholar 

  36. Tsai, H.-H.G., Reches, M., Tsai, C.-J., Gunasekaran, K., Gazit, E., Nussinov, R.: Energy landscape of amyloidogenic peptide oligomerization by parallel-tempering molecular dynamics simulation: significant role of Asn ladder. Proc. Natl. Acad. Sci. USA 102, 8174–8179 (2005)

    Google Scholar 

  37. Wu, K.-P., Weinstock, D.S., Narayanan, C., Levy, R.M., Baum, J.: Structural reorganization of alpha-synuclein at low pH observed by NMR and REMD simulations. J. Mol. Biol. 391, 784–796 (2009)

    Google Scholar 

  38. Li, M.S., Klimov, D.K., Straub, J.E., Thirumalai, D.: Probing the mechanisms of fibril formation using lattice models. J. Chem. Phys. 129, 175101 (2008)

    Google Scholar 

  39. Zhang, J., Muthukumar, M.: Simulations of nucleation and elongation of amyloid fibrils. J. Chem. Phys. 130, 035102 (2009)

    Google Scholar 

  40. Rojas, A., Liwo, A., Browne, D., Scheraga, H.A.: Mechanism of fiber assembly: treatment of Aβ peptide aggregation with a coarse-grained united-residue force field. J. Mol. Biol. 404, 537–552 (2010)

    Google Scholar 

  41. Fawzi, N.L., Chubukov, V., Clark, L.A., Brown, S., Head-Gordon, T.: Influence of denatured and intermediate states of folding on protein aggregation. Protein Sci. 14, 993–1003 (2005)

    Google Scholar 

  42. Auer, S., Dobson, C.M., Vendruscolo, M.: Characterization of the nucleation barriers for protein aggregation and amyloid formation. HFSP J. 1, 137–146 (2007)

    Google Scholar 

  43. Smith, A.V., Hall, C.K.: Protein refolding Versus aggregation: computer simulations on an intermediate-resolution protein model. J. Mol. Biol. 312, 187–202 (2001)

    Google Scholar 

  44. Thirumalai, D., Klimov, D.K., Dima, R.I.: Emerging ideas on the molecular basis of protein and peptide aggregation. Curr. Opin. Struct. Biol. 13, 146–159 (2003)

    Google Scholar 

  45. Janowski, R., Kozak, M., Jankowska, E., Grzonka, Z., Grubb, A., Abrahamson, M., Jaskólski, M.: Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping. Nat. Struct. Mol. Biol. 8, 316–320 (2001)

    Google Scholar 

  46. Bennett, M.J., Sawaya, M.R., Eisenberg, D.: Deposition diseases and 3D domain swapping. Structure 14, 811–824 (2006)

    Google Scholar 

  47. Armen, R.S., DeMarco, M.L., Alonso, D.O.V., Daggett, V.: Pauling and Corey’s alpha-pleated sheet structure define the prefibrillar amyloidogenic intermediate in amyloid disease. Proc. Natl. Acad. Sci. USA 101, 11622–11627 (2004)

    Google Scholar 

  48. Ma, B., Nussinov, R.: The Stability of Monomeric Intermediates Controls Amyloid Formation: Aβ25-35 and its N27Q Mutant. Biophys. J. 90, 3365–3374 (2006)

    Google Scholar 

  49. Gu, W., Wang, T., Zhu, Y., Shi, J., Liu, H.: Molecular dynamics simulation of the unfolding of the human prion protein domain under low pH and high temperature conditions. Biophys. Chem. 104, 79–94 (2003)

    Google Scholar 

  50. Alonso, D.O., Alm, E., Daggett, V.: Characterization of the unfolding pathway of the cell-cycle protein p13suc1 by molecular dynamics simulations: implications for domain swapping. Structure 8, 101–110 (2000)

    Google Scholar 

  51. Gsponer, J., Ferrara, P., Caflisch, A.: Flexibility of the murine prion protein and its Asp178Asn mutant investigated by molecular dynamics simulations. Journal of Molecular Graphics and Modelling 20, 169–182 (2001)

    Google Scholar 

  52. Alonso, D.O., DeArmond, S.J., Cohen, F.E., Daggett, V.: Mapping the early steps in the pH-induced conformational conversion of the prion protein. Proc. Natl. Acad. Sci. USA 98, 2985–2989 (2001)

    Google Scholar 

  53. Yang, M., Lei, M., Bruschweiler, R., Huo, S.: Initial Conformational Changes of Human Transthyretin under Partially Denaturing Conditions. Biophys. J. 89, 11 (2005)

    Google Scholar 

  54. Skoulakis, S., Goodfellow, J.M.: The pH-Dependent Stability of Wild-type and Mutant Transthyretin Oligomers. Biophys. J. 84, 2795–2804 (2003)

    Google Scholar 

  55. Mu, Y., Nordenskiöld, L., Tam, J.P.: Folding, Misfolding, and Amyloid Protofibril Formation of WW Domain FBP28. Biophys. J. 90, 3983–3992 (2006)

    Google Scholar 

  56. Nowak, M.: Immunoglobulin kappa light chain and its amyloidogenic mutants: a molecular dynamics study. Proteins 55, 11–21 (2004)

    Google Scholar 

  57. Prusiner, S.B.: Biology and Genetics of Prion Diseases. Annu. Rev. Microbiol. 48, 655–686 (1994)

    Google Scholar 

  58. Prusiner, S.B.: Neurodegenerative Diseases and Prions. N. Engl. J. Med. 344, 1516–1526 (2001)

    Google Scholar 

  59. Stahl, N., Prusiner, S.B.: Prions and prion protein. FASEB J. 5, 2799–2807 (1991)

    Google Scholar 

  60. Riesner, D.: Biochemistry and structure of PrP(C) and PrP(Sc). Br. Med. Bull. 66, 21–33 (2003)

    Google Scholar 

  61. Zahn, R.: NMR solution structure of the human prion protein. Proceedings of the National Academy of Sciences 97, 145–150 (2000)

    Google Scholar 

  62. Cox, D.L., Lashuel, H., Lee, K.Y.C., Singh, R.R.P.: The Materials Science of Protein Aggregation. MRS Bulletin 30, 452–457 (2005)

    Google Scholar 

  63. Lansbury, P.T., Lashuel, H.A.: A century-old debate on protein aggregation and neurodegeneration enters the clinic. Nature 443, 774–779 (2006)

    Google Scholar 

  64. Dima, R.I., Thirumalai, D.: Exploring the Propensities of Helices in PrPC to Form β Sheet Using NMR Structures and Sequence Alignments. Biophys. J. 83, 1268–1280 (2002)

    Google Scholar 

  65. Lu, X., Wintrode, P.L., Surewicz, W.K.: Beta-sheet core of human prion protein amyloid fibrils as determined by hydrogen/deuterium exchange. Proc. Natl. Acad. Sci. USA 104, 1510–1515 (2007)

    Google Scholar 

  66. Cohen, F.E., Pan, K.M., Huang, Z., Baldwin, M., Fletterick, R.J., Prusiner, S.B.: Structural clues to prion replication. Science 264, 530–531 (1994)

    Google Scholar 

  67. Dima, R.I., Thirumalai, D.: Probing the instabilities in the dynamics of helical fragments from mouse PrPC. Proc. Natl. Acad. Sci. USA 101, 15335–15340 (2004)

    Google Scholar 

  68. Kunes, K.C., Clark, S.C., Cox, D.L., Singh, R.R.P.: Left handed beta helix models for mammalian prion fibrils. Prion 2, 81–90 (2008)

    Google Scholar 

  69. Cobb, N.J., Apetri, A.C., Surewicz, W.K.: Prion protein amyloid formation under native-like conditions involves refolding of the C-terminal alpha-helical domain. J. Biol. Chem. 283, 34704–34711 (2008)

    Google Scholar 

  70. Prusiner, S.B., McKinley, M.P., Bowman, K.A., Bolton, D.C., Bendheim, P.E., Groth, D.F., Glenner, G.G.: Scrapie prions aggregate to form amyloid-like birefringent rods. Cell 35, 349–358 (1983)

    Google Scholar 

  71. El-Bastawissy, E., Knaggs, M.H., Gilbert, I.H.: Molecular dynamics simulations of wild-type and point mutation human prion protein at normal and elevated temperature. Journal of Molecular Graphics and Modelling 20, 145–154 (2001)

    Google Scholar 

  72. Parchment, O.G., Essex, J.W.: Molecular dynamics of mouse and Syrian hamster PrP: implications for activity. Proteins 38, 327–340 (2000)

    Google Scholar 

  73. Zuegg, J., Gready, J.E.: Molecular dynamics simulations of human prion protein: importance of correct treatment of electrostatic interactions. Biochemistry 38, 13862–13876 (1999)

    Google Scholar 

  74. Hornemann, S., Glockshuber, R.: A scrapie-like unfolding intermediate of the prion protein domain PrP(121-231) induced by acidic pH. Proc. Natl. Acad. Sci. USA 95, 6010–6014 (1998)

    Google Scholar 

  75. Swietnicki, W., Morillas, M., Chen, S.G., Gambetti, P., Surewicz, W.K.: Aggregation and fibrillization of the recombinant human prion protein huPrP90-231. Biochemistry 39, 424–431 (2000)

    Google Scholar 

  76. Swietnicki, W., Petersen, R., Gambetti, P., Surewicz, W.K.: pH-dependent stability and conformation of the recombinant human prion protein PrP(90-231). J. Biol. Chem. 272, 27517–27520 (1997)

    Google Scholar 

  77. Zhang, H., Stockel, J., Mehlhorn, I., Groth, D., Baldwin, M.A., Prusiner, S.B., James, T.L., Cohen, F.E.: Physical studies of conformational plasticity in a recombinant prion protein. Biochemistry 36, 3543–3553 (1997)

    Google Scholar 

  78. Jackson, G.S., Hosszu, L.L., Power, A., Hill, A.F., Kenney, J., Saibil, H., Craven, C.J., Waltho, J.P., Clarke, A.R., Collinge, J.: Reversible conversion of monomeric human prion protein between native and fibrilogenic conformations. Science 283, 1935–1937 (1999)

    Google Scholar 

  79. Guo, J., Ren, H., Ning, L., Liu, H., Yao, X.: Exploring structural and thermodynamic stabilities of human prion protein pathogenic mutants D202N, E211Q and Q217R. J. Struct. Biol. 178, 225–232 (2012)

    Google Scholar 

  80. Collinge, J.: Prion diseases of humans and animals: their causes and molecular basis. Annual Review of Neuroscience 24, 519–550 (2001)

    Google Scholar 

  81. Mead, S.: Prion disease genetics. Eur. J. Hum. Genet. 14, 273–281 (2006)

    Google Scholar 

  82. van der Kamp, M.W., Daggett, V.: The consequences of pathogenic mutations to the human prion protein. Protein Eng. Des. Sel. 22, 461–468 (2009)

    Google Scholar 

  83. Rossetti, G., Cong, X., Caliandro, R., Legname, G., Carloni, P.: Common Structural Traits across Pathogenic Mutants of the Human Prion Protein and Their Implications for Familial Prion Diseases. J. Mol. Biol. 411, 700–712 (2011)

    Google Scholar 

  84. Hamilton, J.A., Steinrauf, L.K., Braden, B.C., Liepnieks, J., Benson, M.D., Holmgren, G., Sandgren, O., Steen, L.: The x-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30–>Met variant to 1.7-A resolution. J. Biol. Chem. 268, 2416–2424 (1993)

    Google Scholar 

  85. Sebastião, M.P., Saraiva, M.J., Damas, A.M.: The crystal structure of amyloidogenic Leu55 –> Pro transthyretin variant reveals a possible pathway for transthyretin polymerization into amyloid fibrils. J. Biol. Chem. 273, 24715–24722 (1998)

    Google Scholar 

  86. Cendron, L., Trovato, A., Seno, F., Folli, C., Alfieri, B., Zanotti, G., Berni, R.: Amyloidogenic potential of transthyretin variants: insights from structural and computational analyses. J. Biol. Chem. 284, 25832–25841 (2009)

    Google Scholar 

  87. Hammarström, P.: Trans-Suppression of Misfolding in an Amyloid Disease. Science 293, 2459–2462 (2001)

    Google Scholar 

  88. Hammarström, P., Jiang, X., Hurshman, A.R., Powers, E.T., Kelly, J.W.: Sequence-dependent denaturation energetics: A major determinant in amyloid disease diversity. Proc. Natl. Acad. Sci. USA 99(suppl. 4), 16427–16432 (2002)

    Google Scholar 

  89. Schneider, F., Hammarström, P., Kelly, J.W.: Transthyretin slowly exchanges subunits under physiological conditions: A convenient chromatographic method to study subunit exchange in oligomeric proteins. Protein Sci. 10, 1606–1613 (2001)

    Google Scholar 

  90. Hurshman, A.R., White, J.T., Powers, E.T., Kelly, J.W.: Transthyretin aggregation under partially denaturing conditions is a downhill polymerization. Biochemistry 43, 7365–7381 (2004)

    Google Scholar 

  91. Jiang, X., Smith, C.S., Petrassi, H.M., Hammarström, P., White, J.T., Sacchettini, J.C., Kelly, J.W.: An engineered transthyretin monomer that is nonamyloidogenic, unless it is partially denatured. Biochemistry 40, 11442–11452 (2001)

    Google Scholar 

  92. Armen, R.S., Alonso, D.O.V., Daggett, V.: Anatomy of an Amyloidogenic Intermediate - Conversion of β-Sheet to α-Sheet Structure in Transthyretin at Acidic pH. Structure 12, 1847–1863 (2004)

    Google Scholar 

  93. Liu, K., Cho, H.S., Hoyt, D.W., Nguyen, T.N., Olds, P., Kelly, J.W., Wemmer, D.E.: Deuterium-proton exchange on the native wild-type transthyretin tetramer identifies the stable core of the individual subunits and indicates mobility at the subunit interface. J. Mol. Biol. 303, 555–565 (2000)

    Google Scholar 

  94. Saraiva, M.J.: Transthyretin mutations in hyperthyroxinemia and amyloid diseases. Hum. Mutat. 17, 493–503 (2001)

    Google Scholar 

  95. Lashuel, H.A., Lai, Z., Kelly, J.W.: Characterization of the transthyretin acid denaturation pathways by analytical ultracentrifugation: implications for wild-type, V30M, and L55P amyloid fibril formation. Biochemistry 37, 17851–17864 (1998)

    Google Scholar 

  96. Hörnberg, A., Eneqvist, T., Olofsson, A., Lundgren, E., Sauer-Eriksson, A.E.: A comparative analysis of 23 structures of the amyloidogenic protein transthyretin. J. Mol. Biol. 302, 649–669 (2000)

    Google Scholar 

  97. Wojtczak, A., Neumann, P., Cody, V.: Structure of a new polymorphic monoclinic form of human transthyretin at 3 A resolution reveals a mixed complex between unliganded and T4-bound tetramers of TTR. Acta Crystallogr. D Biol. Crystallogr. 57, 957–967 (2001)

    Google Scholar 

  98. Hörnberg, A., Olofsson, A., Eneqvist, T., Lundgren, E., Sauer-Eriksson, A.E.: The beta-strand D of transthyretin trapped in two discrete conformations. Biochim. Biophys. Acta 1700, 93–104 (2004)

    Google Scholar 

  99. Banerjee, A., Bairagya, H.R., Mukhopadhyay, B.P.B., Nandi, T.K., Bera, A.K.: Structural insight to mutated Y116S transthyretin by molecular dynamics simulation. Indian J. Biochem. Biophys. 47, 197–202 (2010)

    Google Scholar 

  100. Xu, X., Wang, X., Xiao, Z., Li, Y., Wang, Y.: Probing the structural and functional link between mutation- and pH-dependent hydration dynamics and amyloidosis of transthyretin. Soft Matter 8, 324–336 (2011)

    Google Scholar 

  101. Abrahamson, M., Barrett, A.J., Salvesen, G., Grubb, A.: Isolation of six cysteine proteinase inhibitors from human urine. Their physicochemical and enzyme kinetic properties and concentrations in biological fluids. J. Biol. Chem. 261, 11282–11289 (1986)

    Google Scholar 

  102. Grubb, A.O.: Cystatin C-Properties and use as diagnostic marker. In: Advances in Clinical Chemistry, pp. 63–99. Elsevier (2001)

    Google Scholar 

  103. Grzonka, Z., Jankowska, E., Kasprzykowski, F., et al.: Structural studies of cysteine proteases and their inhibitors. Acta Biochim. Pol. 48, 1–20 (2001)

    Google Scholar 

  104. Ghiso, J., Jensson, O., Frangione, B.: Amyloid fibrils in hereditary cerebral hemorrhage with amyloidosis of Icelandic type is a variant of gamma-trace basic protein (cystatin C). Proc. Natl. Acad. Sci. USA 83, 2974–2978 (1986)

    Google Scholar 

  105. Abrahamson, M.: Molecular basis for amyloidosis related to hereditary brain hemorrhage. Scand. J. Clin. Lab. Invest. Suppl. 226, 47–56 (1996)

    Google Scholar 

  106. Olafsson, I., Grubb, A.O.: Hereditary cystatin C amyloid angiopathy. Amyloid 7, 70–79 (2000)

    Google Scholar 

  107. Gerhartz, B., Ekiel, I., Abrahamson, M.: Two stable unfolding intermediates of the disease-causing L68Q variant of human cystatin C. Biochemistry 37, 17309–17317 (1998)

    Google Scholar 

  108. Abrahamson, M., Grubb, A.: Increased body temperature accelerates aggregation of the Leu-68–>Gln mutant cystatin C, the amyloid-forming protein in hereditary cystatin C amyloid angiopathy. Proc. Natl. Acad. Sci. USA 91, 1416–1420 (1994)

    Google Scholar 

  109. Jankowska, E., Wiczk, W., Grzonka, Z.: Thermal and guanidine hydrochloride-induced denaturation of human cystatin C. Eur. Biophys. J. 33, 454–461 (2004)

    Google Scholar 

  110. Nilsson, M., Wang, X., Rodziewicz-Motowidlo, S., Janowski, R., Lindström, V., Onnerfjord, P., Westermark, G., Grzonka, Z., Jaskolski, M.M., Grubb, A.A.: Prevention of domain swapping inhibits dimerization and amyloid fibril formation of cystatin C: use of engineered disulfide bridges, antibodies, and carboxymethylpapain to stabilize the monomeric form of cystatin C. J. Biol. Chem. 279, 24236–24245 (2004)

    Google Scholar 

  111. Liu, H.-L., Lin, Y.-M., Zhao, J.-H., Hsieh, M.-C., Lin, H.-Y., Huang, C.-H., Fang, H.-W., Ho, Y., Chen, W.-Y.: Molecular dynamics simulations of human cystatin C and its L68Q varient to investigate the domain swapping mechanism. J. Biomol. Struct. Dyn. 25, 135–144 (2007)

    Google Scholar 

  112. Lin, Y.-M., Liu, H.-L., Zhao, J.-H., Huang, C.-H., Fang, H.-W., Ho, Y., Chen, W.-Y.: Molecular Dynamics Simulations to Investigate the Domain Swapping Mechanism of Human Cystatin C. Biotechnol. Progress 23, 577–584 (2008)

    Google Scholar 

  113. Yu, Y., Wang, Y., He, J., Liu, Y., Li, H., Zhang, H., Song, Y.: Structural and dynamic properties of a new amyloidogenic chicken cystatin mutant I108T. J. Biomol. Struct. Dyn. 27, 641–649 (2010)

    Google Scholar 

  114. Ekiel, I., Abrahamson, M., Fulton, D.B., et al.: NMR structural studies of human cystatin C dimers and monomers. J. Mol. Biol. 271, 266–277 (1997)

    Google Scholar 

  115. Sinha, N., Tsai, C.J., Nussinov, R.: A proposed structural model for amyloid fibril elongation: domain swapping forms an interdigitating beta-structure polymer. Protein Eng. 14, 93–103 (2001)

    Google Scholar 

  116. Staniforth, R.A., Giannini, S., Higgins, L.D., Conroy, M.J., Hounslow, A.M., Jerala, R., Craven, C.J., Waltho, J.P.: Three-dimensional domain swapping in the folded and molten-globule states of cystatins, an amyloid-forming structural superfamily. EMBO J. 20, 4774–4781 (2001)

    Google Scholar 

  117. Stubbs, M.T., Laber, B., Bode, W., Huber, R., Jerala, R., Lenarcic, B., Turk, V.: The refined 2.4 A X-ray crystal structure of recombinant human stefin B in complex with the cysteine proteinase papain: a novel type of proteinase inhibitor interaction. EMBO J. 9, 1939–1947 (1990)

    Google Scholar 

  118. Engh, R.A., Dieckmann, T., Bode, W., Auerswald, E.A., Turk, V., Huber, R., Oschkinat, H.: Conformational variability of chicken cystatin. Comparison of structures determined by X-ray diffraction and NMR spectroscopy. J. Mol. Biol. 234, 1060–1069 (1993)

    Google Scholar 

  119. Rodziewicz-Motowidło, S., Iwaszkiewicz, J., Sosnowska, R., Czaplewska, P., Sobolewski, E., Szymańska, A., Stachowiak, K., Liwo, A.: The role of the Val57 amino-acid residue in the hinge loop of the human cystatin C. Conformational studies of the beta2-L1-beta3 segments of wild-type human cystatin C and its mutants. Biopolymers 91, 373–383 (2009)

    Google Scholar 

  120. Sunde, M., Serpell, L.C., Bartlam, M., Fraser, P.E., Pepys, M.B., Blake, C.C.: Common core structure of amyloid fibrils by synchrotron X-ray diffraction. J. Mol. Biol. 273, 729–739 (1997)

    Google Scholar 

  121. Blake, C., Serpell, L.: Synchrotron X-ray studies suggest that the core of the transthyretin amyloid fibril is a continuous β-sheet helix. Structure 4, 989–998 (1996)

    Google Scholar 

  122. Cohen, A.S., Shirahama, T., Skinner, M.: Electron microscopy of amyloid. Electron Microscopy of Proteins 3, 165–205 (1982)

    Google Scholar 

  123. Puchtler, H., Sweat, F.: Congo red as a stain for fluorescence microscopy of amyloid. J. Histochem. Cytochem. 13, 693–694 (1965)

    Google Scholar 

  124. Chiti, F., Dobson, C.M.: Protein misfolding, functional amyloid, and human disease. Annu. Rev. Biochem. 75, 333–366 (2006)

    Google Scholar 

  125. Serpell, L.C., Sunde, M., Benson, M.D., Tennent, G.A., Pepys, M.B., Fraser, P.E.: The protofilament substructure of amyloid fibrils. J. Mol. Biol. 300, 1033–1039 (2000)

    Google Scholar 

  126. Nelson, R., Eisenberg, D.: Recent atomic models of amyloid fibril structure. Curr. Opin. Struct. Biol. 16, 260–265 (2006)

    Google Scholar 

  127. Jiménez, J.L., Guijarro, J.I., Orlova, E., Zurdo, J., Dobson, C.M., Sunde, M., Saibil, H.R.: Cryo-electron microscopy structure of an SH3 amyloid fibril and model of the molecular packing. EMBO J. 18, 815–821 (1999)

    Google Scholar 

  128. Govaerts, C., Wille, H., Prusiner, S.B., Cohen, F.E.: Evidence for assembly of prions with left-handed beta-helices into trimers. Proc. Natl. Acad. Sci. USA 101, 8342–8347 (2004)

    Google Scholar 

  129. Sikorski, P., Atkins, E.: New model for crystalline polyglutamine assemblies and their connection with amyloid fibrils. Biomacromolecules 6, 425–432 (2005)

    Google Scholar 

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

    Google Scholar 

  131. Serag, A.A., Altenbach, C., Gingery, M., Hubbell, W.L., Yeates, T.O.: Arrangement of subunits and ordering of beta-strands in an amyloid sheet. Nat. Struct. Biol. 9, 734–739 (2002)

    Google Scholar 

  132. Ivanova, M.I., Sawaya, M.R., Gingery, M., Attinger, A., Eisenberg, D.: An amyloid-forming segment of beta2-microglobulin suggests a molecular model for the fibril. Proc. Natl. Acad. Sci. USA 101, 10584–10589 (2004)

    Google Scholar 

  133. Gronenborn, A.M.: Protein acrobatics in pairs—dimerization via domain swapping. Curr. Opin. Struct. Biol. 19, 39–49 (2009)

    Google Scholar 

  134. la Paz de, M.L., de Mori, G.M.S., Serrano, L., Colombo, G.: Sequence Dependence of Amyloid Fibril Formation: Insights from Molecular Dynamics Simulations. J. Mol. Biol. 349, 583–596 (2005)

    Google Scholar 

  135. Li, L., Darden, T.A., Bartolotti, L., Kominos, D., Pedersen, L.G.: An atomic model for the pleated beta-sheet structure of Abeta amyloid protofilaments. Biophys. J. 76, 2871–2878 (1999)

    Google Scholar 

  136. Zanuy, D., Nussinov, R.: The Sequence Dependence of Fiber Organization. A Comparative Molecular Dynamics Study of the Islet Amyloid Polypeptide Segments 22-27 and 22-29. J. Mol. Biol. 329, 565–584 (2003)

    Google Scholar 

  137. Tsai, H.H., Zanuy, D., Haspel, N., Gunasekaran, K., Ma, B., Tsai, C.J., Nussinov, R.: The stability and dynamics of the human calcitonin amyloid peptide DFNKF. Biophys. J. 87, 146–158 (2004)

    Google Scholar 

  138. Ye, W., Chen, Y., Wang, W., Yu, Q., Li, Y., Zhang, J., Chen, H.-F.: Insight into the stability of cross-β amyloid fibril from VEALYL short peptide with molecular dynamics simulation. PLoS ONE 7, e36382 (2012)

    Google Scholar 

  139. Periole, X., Rampioni, A., Vendruscolo, M., Mark, A.E.: Factors That Affect the Degree of Twist in beta-Sheet Structures: A Molecular Dynamics Simulation Study of a Cross-beta Filament of the GNNQQNY Peptide. J. Phys. Chem. B 113, 1728–1737 (2009)

    Google Scholar 

  140. Song, W., Wei, G., Mousseau, N., Derreumaux, P.: Self-assembly of the beta2-microglobulin NHVTLSQ peptide using a coarse-grained protein model reveals a beta-barrel species. J. Phys. Chem. B 112, 4410–4418 (2008)

    Google Scholar 

  141. Berryman, J.T., Radford, S.E., Harris, S.A.: Systematic Examination of Polymorphism in Amyloid Fibrils by Molecular-Dynamics Simulation. Biophys. J. 100, 2234–2242 (2011)

    Google Scholar 

  142. Connelly, L., Jang, H., Arce, F.T., Capone, R., Kotler, S.A., Ramachandran, S., Kagan, B.L., Nussinov, R., Lal, R.: Atomic Force Microscopy and MD Simulations Reveal Pore-Like Structures of All-d-Enantiomer of Alzheimer’s β-Amyloid Peptide: Relevance to the Ion Channel Mechanism of AD Pathology. J. Phys. Chem. B 116, 1728–1735 (2012)

    Google Scholar 

  143. Kent, A., Jha, A.K., Fitzgerald, J.E., Freed, K.F.: Benchmarking implicit solvent folding simulations of the amyloid beta(10-35) fragment. J. Phys. Chem. B 112, 6175–6186 (2008)

    Google Scholar 

  144. Zheng, J., Jang, H., Nussinov, R.: Beta2-microglobulin amyloid fragment organization and morphology and its comparison to Abeta suggests that amyloid aggregation pathways are sequence specific. Biochemistry 47, 2497–2509 (2008)

    Google Scholar 

  145. Wang, J., Tan, C., Chen, H.-F., Luo, R.: All-Atom Computer Simulations of Amyloid Fibrils Disaggregation. Biophys. J. 95, 5037–5047 (2008)

    Google Scholar 

  146. Gnanakaran, S., Nussinov, R., García, A.E.: Atomic-level description of amyloid beta-dimer formation. J. Am. Chem. Soc. 128, 2158–2159 (2006)

    Google Scholar 

  147. Boucher, G., Mousseau, N., Derreumaux, P.: Aggregating the amyloid Abeta(11-25) peptide into a four-stranded beta-sheet structure. Proteins 65, 877–888 (2006)

    Google Scholar 

  148. Lipfert, J., Franklin, J., Wu, F., Doniach, S.: Protein Misfolding and Amyloid Formation for the Peptide GNNQQNY from Yeast Prion Protein Sup35: Simulation by Reaction Path Annealing. J. Mol. Biol. 349, 648–658 (2005)

    Google Scholar 

  149. Soto, P., Cladera, J., Mark, A.E., Daura, X.: Stability of SIV gp32 Fusion-Peptide Single-Layer Protofibrils as Monitored by Molecular-Dynamics Simulations. Angew Chem. 117, 1089–1091 (2005)

    Google Scholar 

  150. Correia, B.E., Loureiro-Ferreira, N., Rodrigues, J.R., Brito, R.M.M.: A structural model of an amyloid protofilament of transthyretin. Protein Sci. 15, 28–32 (2005)

    Google Scholar 

  151. Colombo, G., Meli, M., De Simone, A.: Computational studies of the structure, dynamics and native content of amyloid- like fibrils of ribonuclease A. Proteins 70, 863–872 (2007)

    Google Scholar 

  152. Gohlke, H., Kiel, C., Case, D.A.: Insights into protein-protein binding by binding free energy calculation and free energy decomposition for the Ras-Raf and Ras-RalGDS complexes. J. Mol. Biol. 330, 891–913 (2003)

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculty of Chemistry, University of Gdańsk, Sobieskego 18, Gdańsk, Poland

    Sylwia Rodziewicz-Motowidło & Emilia Sikorska

  2. Swiss Institute of Bioinformatics, Molecular Modeling Group, Bâtiment Genopode, Quartier Sorge, 1015, Lausanne, Switzerland

    Justyna Iwaszkiewicz

Authors
  1. Sylwia Rodziewicz-Motowidło
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emilia Sikorska
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Justyna Iwaszkiewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sylwia Rodziewicz-Motowidło .

Editor information

Editors and Affiliations

  1. , Faculty of Chemistry, University of Gdansk, Sobieskiego 18, Gdansk, 80-952, Poland

    Adam Liwo

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Rodziewicz-Motowidło, S., Sikorska, E., Iwaszkiewicz, J. (2014). Molecular Dynamics Studies on Amyloidogenic Proteins. In: Liwo, A. (eds) Computational Methods to Study the Structure and Dynamics of Biomolecules and Biomolecular Processes. Springer Series in Bio-/Neuroinformatics, vol 1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-28554-7_14

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-28554-7_14

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-28553-0

  • Online ISBN: 978-3-642-28554-7

  • eBook Packages: EngineeringEngineering (R0)

Publish with us

Policies and ethics

Search

Navigation