Skip to main content
SpringerLink
Log in

Dynamics of Amyloid Formation from Simplified Representation to Atomistic Simulations

  • Protocol
  • First Online:
Computational Peptide Science

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2405))

Abstract

Amyloid fibril formation is an intrinsic property of short peptides, non-disease proteins, and proteins associated with neurodegenerative diseases. Aggregates of the Aβ and tau proteins, the α-synuclein protein, and the prion protein are observed in the brain of Alzheimer’s, Parkinson’s, and prion disease patients, respectively. Due to the transient short-range and long-range interactions of all species and their high aggregation propensities, the conformational ensemble of these devastating proteins, the exception being for the monomeric prion protein, remains elusive by standard structural biology methods in bulk solution and in lipid membranes. To overcome these limitations, an increasing number of simulations using different sampling methods and protein models have been performed. In this chapter, we first review our main contributions to the field of amyloid protein simulations aimed at understanding the early aggregation steps of short linear amyloid peptides, the conformational ensemble of the Aβ40/42 dimers in bulk solution, and the stability of Aβ aggregates in lipid membrane models. Then we focus on our studies on the interactions of amyloid peptides/inhibitors to prevent aggregation, and long amyloid sequences, including new results on a monomeric tau construct.

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

Access this chapter

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

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Goldberg MS, Lansbury PT Jr (2000) Is there a cause-and-effect relationship between alpha-synuclein fibrillization and Parkinson’s disease? Nat Cell Biol 2:E115–E119

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  3. Scheckel C, Aguzzi A (2018) Prions, prionoids and protein misfolding disorders. Nat Rev Genet 19:405–418

    CAS  PubMed  Google Scholar 

  4. Barthélemy NR, Li Y, Joseph-Mathurin N, Gordon BA, Hassenstab J, Benzinger TLS, Buckles V, Fagan AM, Perrin RJ, Goate AM et al (2020) Dominantly Inherited Alzheimer Network. A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease. Nat Med 26:398–407

    PubMed  PubMed Central  Google Scholar 

  5. Auluck PK, Caraveo G, Lindquist S (2010) Alpha-Synuclein: membrane interactions and toxicity in Parkinson’s disease. Annu Rev Cell Dev Biol 26:211–233

    CAS  PubMed  Google Scholar 

  6. Riek R, Hornemann S, Wider G, Billeter M, Glockshuber R, Wuthrich K (1996) NMR structure of the mouse prion protein domain PrP(121-321). Nature 382:180–182

    CAS  PubMed  Google Scholar 

  7. Dobson CM (1999) Protein misfolding, evolution and disease. Trends Biochem Sci 24:329–332

    CAS  PubMed  Google Scholar 

  8. Lu JX, Qiang W, Yau WM, Schwieters CD, Meredith SC, Tycko R (2013) Molecular structure of β-amyloid fibrils in Alzheimer’s disease brain tissue. Cell 154:1257–1268

    CAS  PubMed  Google Scholar 

  9. Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, Crowther RA, Ghetti B, Goedert M, Scheres SHW (2017) Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547:185–190

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Guerrero-Ferreira R, Taylor NM, Mona D, Ringler P, Lauer ME, Riek R, Britschgi M, Stahlberg H (2018) Cryo-EM structure of alpha-synuclein fibrils. elife 7:e36402

    PubMed  PubMed Central  Google Scholar 

  11. Meisl G, Michaels TCT, Linse S, Knowles TPJ (2018) Kinetic analysis of amyloid formation. Methods Mol Biol 1779:181–196

    CAS  PubMed  Google Scholar 

  12. Buttstedt A, Wostradowski T, Ihling C, Hause G, Sinz A, Schwarz E (2013) Different morphology of amyloid fibrils originating from agitated and non-agitated conditions. Amyloid 2:86–92

    Google Scholar 

  13. Luo XD, Kong FL, Dang HB, Chen J, Liang Y (2016) Macromolecular crowding favors the fibrillization of β2-microglobulin by accelerating the nucleation step and inhibiting fibril disassembly. Biochim Biophys Acta 1864:1609–1619

    CAS  PubMed  Google Scholar 

  14. Xu W, Zhang C, Derreumaux P, Gräslund A, Morozova-Roche L, Mu Y (2011) Intrinsic determinants of Aβ(12-24) pH-dependent self-assembly revealed by combined computational and experimental studies. PLoS One 6:e24329

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Habchi J, Chia S, Galvagnion C, Michaels TCT, Bellaiche MMJ, Ruggeri FS, Sanguanini M, Idini I, Kumita JR, Sparr E et al (2018) Cholesterol catalyses Aβ42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes. Nat Chem 10:673–683

    CAS  PubMed  Google Scholar 

  16. Sibille N, Sillen A, Leroy A, Wieruszeski JM, Mulloy B, Landrieu I, Lippens G (2006) Structural impact of heparin binding to full-length Tau as studied by NMR spectroscopy. Biochemistry 45:12560–12572

    CAS  PubMed  Google Scholar 

  17. Balbach JJ, Ishii Y, Antzutkin ON, Leapman RD, Rizzo NW, Dyda F, Reed J, Tycko R (2000) Amyloid fibril formation by A beta 16-22, a seven-residue fragment of the Alzheimer’s beta-amyloid peptide, and structural characterization by solid state NMR. Biochemistry 39:13748–13759

    CAS  PubMed  Google Scholar 

  18. Inouye H, Sharma D, Goux WJ, Kirschner DA (2006) Structure of core domain of fibril-forming PHF/Tau fragments. Biophys J 90:1774–1789

    CAS  PubMed  Google Scholar 

  19. Bodles AM, Guthrie DJ, Greer B, Irvine GB (2001) Identification of the region of non-Abeta component (NAC) of Alzheimer’s disease amyloid responsible for its aggregation and toxicity. J Neurochem 78:384–395

    CAS  PubMed  Google Scholar 

  20. Mousseau N, Derreumaux P (2005) Exploring the early steps of amyloid peptide aggregation by computers. Acc Chem Res 38:885–891

    CAS  PubMed  Google Scholar 

  21. Nasica-Labouze J, Nguyen PH, Sterpone F, Berthoumieu O, Buchete NV, Coté S, De Simone A, Doig AJ, Faller P, Garcia A et al (2015) Amyloid beta protein and Alzheimer’s disease: when computer simulations complement experimental studies. Chem Rev 115:3518–3563

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Lasagna-Reeves CA, Castillo-Carranza DL, Guerrero-Muoz MJ, Jackson GR, Kayed R (2010) Preparation and characterization of neurotoxic tau oligomers. Biochemistry 49:10039–10041

    CAS  PubMed  Google Scholar 

  23. Fusco G, Chen SW, Williamson PTF, Cascella R, Perni M, Jarvis JA, Cecchi C, Vendruscolo M, Chiti F, Cremades N et al (2017) Structural basis of membrane disruption and cellular toxicity by α-synuclein oligomers. Science 2017(358):1440–1443

    Google Scholar 

  24. Graen T, Klement R, Grupi A, Haas E, Grubmüller H (2018) Transient secondary and tertiary structure formation kinetics in the intrinsically disordered state of α-synuclein from atomistic simulations. ChemPhysChem 19:2507–2511

    CAS  PubMed  Google Scholar 

  25. Nguyen PH, Derreumaux P (2020) Structures of the intrinsically disordered Aβ, tau and α-synuclein proteins in aqueous solution from computer simulations. Biophys Chem 264:106421

    CAS  PubMed  Google Scholar 

  26. Santini S, Wei G, Mousseau N, Derreumaux P (2004) Pathway complexity of Alzheimer’s beta-amyloid Abeta16-22 peptide assembly. Structure 12:1245–1255

    CAS  PubMed  Google Scholar 

  27. Santini S, Mousseau N, Derreumaux P (2004) In silico assembly of Alzheimer’s Abeta16-22 peptide into beta-sheets. J Am Chem Soc 126:11509–11516

    CAS  PubMed  Google Scholar 

  28. Wei G, Mousseau N, Derreumaux P (2004) Sampling the self-assembly pathways of KFFE hexamers. Biophys J 87:3648–3656

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Melquiond A, Boucher G, Mousseau N, Derreumaux P (2005) Following the aggregation of amyloid-forming peptides by computer simulations. J Chem Phys 122:174904

    PubMed  Google Scholar 

  30. Melquiond A, Mousseau N, Derreumaux P (2006) Structures of soluble amyloid oligomers from computer simulations. Proteins 65:180–191

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  32. Melquiond A, Gelly JC, Mousseau N, Derreumaux P (2007) Probing amyloid fibril formation of the NFGAIL peptide by computer simulations. J Chem Phys 126:065101

    PubMed  Google Scholar 

  33. Man VH, He X, Derreumaux P, Ji B, Xie XQ, Nguyen PH, Wang J (2019) Effects of all-atom molecular mechanics force fields on amyloid peptide assembly: the case of Aβ16-22 dimer. J Chem Theory Comput 15:1440–1452

    PubMed  PubMed Central  Google Scholar 

  34. Mo Y, Lu Y, Wei G, Derreumaux P (2009) Structural diversity of the soluble trimers of the human amylin(20-29) peptide revealed by molecular dynamics simulations. J Chem Phys 130:125101

    PubMed  Google Scholar 

  35. Lu Y, Derreumaux P, Guo Z, Mousseau N, Wei G (2009) Thermodynamics and dynamics of amyloid peptide oligomerization are sequence dependent. Proteins 75:954–963

    CAS  PubMed  Google Scholar 

  36. Wei G, Song W, Derreumaux P, Mousseau N (2008) Self-assembly of amyloid-forming peptides by molecular dynamics simulations. Front Biosci 13:5681–5692

    CAS  PubMed  Google Scholar 

  37. Song W, Wei G, Mousseau N, Derreumaux P (2008) 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

    CAS  PubMed  Google Scholar 

  38. Nguyen PH, Li MS, Derreumaux P (2011) Effects of all-atom force fields on amyloid oligomerization: replica exchange molecular dynamics simulations of the Aβ(16-22) dimer and trimer. Phys Chem Chem Phys 13:9778–9788

    CAS  PubMed  Google Scholar 

  39. De Simone A, Derreumaux P (2010) Low molecular weight oligomers of amyloid peptides display beta-barrel conformations: a replica exchange molecular dynamics study in explicit solvent. J Chem Phys 132:165103

    PubMed  Google Scholar 

  40. Nguyen PH, Derreumaux P (2013) Conformational ensemble and polymorphism of the all-atom Alzheimer’s Aβ(37-42) amyloid peptide oligomers. J Phys Chem B 117:5831–5840

    CAS  PubMed  Google Scholar 

  41. Spill YG, Pasquali S, Derreumaux P (2011) Impact of thermostats on folding and aggregation properties of peptides using the optimized potential for efficient structure prediction coarse-grained model. J Chem Theory Comput 7:1502–1510

    CAS  PubMed  Google Scholar 

  42. Nasica-Labouze J, Meli M, Derreumaux P, Colombo G, Mousseau N (2011) A multiscale approach to characterize the early aggregation steps of the amyloid-forming peptide GNNQQNY from the yeast prion sup-35. PLoS Comput Biol 7:e1002051

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Lu Y, Wei G, Derreumaux P (2012) Structural, thermodynamical, and dynamical properties of oligomers formed by the amyloid NNQQ peptide: insights from coarse-grained simulations. J Chem Phys 137:025101

    PubMed  Google Scholar 

  44. Nguyen PH, Okamoto Y, Derreumaux P (2013) Communication: simulated tempering with fast on-the-fly weight determination. J Chem Phys 138:061102

    PubMed  Google Scholar 

  45. Chebaro Y, Pasquali S, Derreumaux P (2012) The coarse-grained OPEP force field for non-amyloid and amyloid proteins. J Phys Chem B 116:8741–8752

    CAS  PubMed  Google Scholar 

  46. Wei G, Mousseau N, Derreumaux P (2007) Computational simulations of the early steps of protein aggregation. Prion 1:3–8

    PubMed  PubMed Central  Google Scholar 

  47. Derreumaux P (1999) From polypeptide sequences to structures using Monte Carlo simulations and an optimized potential. J Chem Phys 5:2301–2310

    Google Scholar 

  48. Derreumaux P (2001) Generating ensemble averages for small proteins from extended conformations by Monte Carlo simulations. Phys Rev Lett 1:206–209

    Google Scholar 

  49. Maupetit J, Tuffery P, Derreumaux P (2007) A coarse-grained protein force field for folding and structure prediction. Proteins 69:394–408

    CAS  PubMed  Google Scholar 

  50. Sterpone F, Nguyen PH, Kalimeri M, Derreumaux P (2013) Importance of the ion-pair interactions in the OPEP coarse-grained force field: parametrization and validation. J Chem Theory Comput 9:4574–4584

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Sterpone F, Melchionna S, Tuffery P, Pasquali S, Mousseau N, Cragnolini T, Chebaro Y, St-Pierre JF, Kalimeri M, Barducci A et al (2014) The OPEP protein model: from single molecules, amyloid formation, crowding and hydrodynamics to DNA/RNA systems. Chem Soc Rev 43:4871–4893

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Kalimeri M, Derreumaux P, Sterpone F (2015) Are coarse-grained models apt to detect protein thermal stability? The case of OPEP force field. J Non-Cryst Solids 407:494–501

    CAS  PubMed  Google Scholar 

  53. Mousseau N, Derreumaux P, Barkema GT, Malek R (2001) Sampling activated mechanisms in proteins with the activation-relaxation technique. J Mol Graph Model 19:78–86

    CAS  PubMed  Google Scholar 

  54. Wei GH, Derreumaux P, Mousseau N (2003) Sampling the complex energy landscape of a simple beta-hairpin. J Chem Phys 13:6403–6406

    Google Scholar 

  55. Mousseau N, Derreumaux P (2008) Exploring energy landscapes of protein folding and aggregation. Front Biosci 13:4495–44516

    CAS  PubMed  Google Scholar 

  56. Kreutzer AG, Nowick JS (2018) Elucidating the structures of amyloid oligomers with macrocyclic β-hairpin peptides: insights into Alzheimer’s disease and other amyloid diseases. Acc Chem Res 51:706–718

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Laganowsky A, Liu C, Sawaya MR, Whitelegge JP, Park J, Zhao M, Pensalfini A, Soriaga AB, Landau M, Teng PK et al (2012) Atomic view of a toxic amyloid small oligomer. Science 335:1228–1231

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Matthes D, Gapsys V, Brennecke JT, de Groot BL (2016) An atomistic view of amyloidogenic self-assembly: structure and dynamics of heterogeneous conformational states in the pre-nucleation phase. Sci Rep 6:33156

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Levine ZA, Shea JE (2017) Simulations of disordered proteins and systems with conformational heterogeneity. Curr Opin Struct Biol 43:95–103

    CAS  PubMed  Google Scholar 

  60. Decatur SM (2006) Elucidation of residue-level structure and dynamics of polypeptides via isotope-edited infrared spectroscopy. Acc Chem Res 39:169–175

    CAS  PubMed  Google Scholar 

  61. Jia Z, Schmit JD, Chen J (2020) Amyloid assembly is dominated by misregistered kinetic traps on an unbiased energy landscape. Proc Natl Acad Sci U S A 117:10322–10328

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Samantray S, Yin F, Kav B, Strodel B (2020) Different force fields give rise to different amyloid aggregation pathways in molecular dynamics simulations. J Chem Inf Model 60:6462–6475

    CAS  PubMed  Google Scholar 

  63. Robustelli P, Piana S, Shaw DE (2018) Developing a molecular dynamics force field for both folded and disordered protein states. Proc Natl Acad Sci U S A 115:E4758–E4766

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Rahman MU, Rehman AU, Liu H, Chen HF (2020) Comparison and evaluation of force fields for intrinsically disordered proteins. J Chem Inf Model 60:4912–4923

    CAS  PubMed  Google Scholar 

  65. Huang J, Rauscher S, Nawrocki G, Ran T, Feig M, de Groot BL, Grubmüller H, MacKerell AD Jr (2017) CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nat Methods 14:71–73

    CAS  PubMed  Google Scholar 

  66. Carballo-Pacheco M, Ismail AE, Strodel B (2018) On the applicability of force fields to study the aggregation of amyloidogenic peptides using molecular dynamics simulations. J Chem Theory Comput 14:6063–6075

    CAS  PubMed  Google Scholar 

  67. Baftizadeh F, Pietrucci F, Biarnés X, Laio A (2013) Nucleation process of a fibril precursor in the C-terminal segment of amyloid-β. Phys Rev Lett 110:168103

    PubMed  Google Scholar 

  68. Šarić A, Michaels TCT, Zaccone A, Knowles TPJ, Frenkel D (2016) Kinetics of spontaneous filament nucleation via oligomers: insights from theory and simulation. J Chem Phys 145:211926

    PubMed  Google Scholar 

  69. Lee CT, Terentjev EM (2017) Mechanisms and rates of nucleation of amyloid fibrils. J Chem Phys 147:105103

    PubMed  Google Scholar 

  70. Nguyen P, Derreumaux P (2014) Understanding amyloid fibril nucleation and aβ oligomer/drug interactions from computer simulations. Acc Chem Res 47:603–611

    CAS  PubMed  Google Scholar 

  71. Tran TT, Nguyen PH, Derreumaux P (2016) Lattice model for amyloid peptides: OPEP force field parametrization and applications to the nucleus size of Alzheimer’s peptides. J Chem Phys 144:205103

    PubMed  Google Scholar 

  72. Chiricotto M, Tran TT, Nguyen PH, Melchionna S, Sterpone F, Derreumaux P (2017) Coarse-grained and all-atom simulations towards the early and late steps of amyloid fibril formation. Isr J Chem 57:564–573

    CAS  Google Scholar 

  73. Sterpone F, Doutreligne S, Tran TT, Melchionna S, Baaden M, Nguyen PH, Derreumaux P (2018) Multiscale simulations of biological systems using the OPEP coarse-grained model. Biochem Biophys Res Commun 498:296–304

    CAS  PubMed  Google Scholar 

  74. Szała-Mendyk B, Molski A (2020) Clustering and fibril formation during GNNQQNY aggregation: a molecular dynamics study. Biomol Ther 10:1362

    Google Scholar 

  75. Villali J, Dark J, Brechtel TM, Pei F, Sindi SS, Serio TR (2020) Nucleation seed size determines amyloid clearance and establishes a barrier to prion appearance in yeast. Nat Struct Mol Biol 27:540–549

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Sterpone F, Derreumaux P, Melchionna S (2015) Protein simulations in fluids: coupling the OPEP coarse-grained force field with hydrodynamics. J Chem Theory Comput 11:1843–1853

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Chiricotto M, Sterpone F, Derreumaux P, Melchionna S (2016) Multiscale simulation of molecular processes in cellular environments. Philos Trans A Math Phys Eng Sci 374:20160225

    PubMed  PubMed Central  Google Scholar 

  78. Chiricotto M, Melchionna S, Derreumaux P, Sterpone F (2016) Hydrodynamic effects on β-amyloid (16-22) peptide aggregation. J Chem Phys 145:035102

    PubMed  Google Scholar 

  79. Chiricotto M, Melchionna S, Derreumaux P, Sterpone F (2019) Multiscale aggregation of the amyloid Aβ16-22 peptide: from disordered coagulation and lateral branching to amorphous prefibrils. J Phys Chem Lett 10:1594–1599

    CAS  PubMed  Google Scholar 

  80. Nguyen PH, Sterpone F, Derreumaux P (2020) Aggregation of disease-related peptides. Prog Mol Biol Transl Sci 170:435–460

    PubMed  Google Scholar 

  81. Lasagna-Reeves CA, Glabe CG, Kayed R (2011) Amyloid-β annular protofibrils evade fibrillar fate in Alzheimer disease brain. J Biol Chem 286:22122–22130

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Lesné SE, Sherman MA, Grant M, Kuskowski M, Schneider JA, Bennett DA, Ashe KH (2013) Brain amyloid-β oligomers in ageing and Alzheimer’s disease. Brain 136:1383–1398

    PubMed  PubMed Central  Google Scholar 

  83. Müller-Schiffmann A, Andreyeva A, Horn AH, Gottmann K, Korth C, Sticht H (2011) Molecular engineering of a secreted, highly homogeneous, and neurotoxic Aβ dimer. ACS Chem Neurosci 2:242–248

    PubMed  PubMed Central  Google Scholar 

  84. Rousseau F, Schymkowitz J, De Strooper B (2014) The Alzheimer disease protective mutation A2T modulates kinetic and thermodynamic properties of amyloid-β (Aβ) aggregation. J Biol Chem 289:30977–30989

    PubMed  PubMed Central  Google Scholar 

  85. Zheng X, Liu D, Roychaudhuri R, Teplow DB, Bowers MT (2015) Amyloid β-protein assembly: differential effects of the protective A2T mutation and recessive A2V familial Alzheimer’s disease mutation. ACS Chem Neurosci 6:1732–1740

    CAS  PubMed  Google Scholar 

  86. Messa M, Colombo L, del Favero E, Cantù L, Stoilova T, Cagnotto A, Rossi A, Morbin M, Di Fede G, Tagliavini F et al (2014) The peculiar role of the A2V mutation in amyloid-β (Aβ) 1-42 molecular assembly. J Biol Chem 289:24143–24152

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Tarus B, Tran TT, Nasica-Labouze J, Sterpone F, Nguyen PH, Derreumaux P (2015) Structures of the Alzheimer’s wild-type Aβ1-40 dimer from atomistic simulations. J Phys Chem B 119:10478–10487

    CAS  PubMed  Google Scholar 

  88. Man VH, Nguyen PH, Derreumaux P (2017) High-resolution structures of the amyloid-β 1-42 dimers from the comparison of four atomistic force fields. J Phys Chem B 121:5977–5987

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Côté S, Derreumaux P, Mousseau N (2011) Distinct morphologies for amyloid beta protein monomer: Aβ1-40, Aβ1-42, and Aβ1-40(D23N). J Chem Theory Comput 7:2584–2592

    PubMed  Google Scholar 

  90. Côté S, Laghaei R, Derreumaux P, Mousseau N (2012) Distinct dimerization for various alloforms of the amyloid-beta protein: Aβ(1-40), Aβ(1-42), and Aβ(1-40)(D23N). J Phys Chem B 116:4043–4055

    PubMed  Google Scholar 

  91. Cao Y, Jiang X, Han W (2017) Self-assembly pathways of β-sheet-rich amyloid-β(1-40) dimers: markov state model analysis on millisecond hybrid-resolution simulations. J Chem Theory Comput 13:5731–5744

    CAS  PubMed  Google Scholar 

  92. Chebaro Y, Mousseau N, Derreumaux P (2009) Structures and thermodynamics of Alzheimer’s amyloid-beta Abeta(16-35) monomer and dimer by replica exchange molecular dynamics simulations: implication for full-length Abeta fibrillation. J Phys Chem B 113:7668–7675

    CAS  PubMed  Google Scholar 

  93. Man VH, Nguyen PH, Derreumaux P (2017) Conformational ensembles of the wild-type and S8C Aβ1-42 Dimers. J Phys Chem B 121:2434–2442

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Viet MH, Nguyen PH, Derreumaux P, Li MS (2014) Effect of the English familial disease mutation (H6R) on the monomers and dimers of Aβ40 and Aβ42. ACS Chem Neurosci 5:646–657

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Viet MH, Nguyen PH, Ngo ST, Li MS, Derreumaux P (2013) Effect of the Tottori familial disease mutation (D7N) on the monomers and dimers of Aβ40 and Aβ42. ACS Chem Neurosci 4:1446–1457

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Huet A, Derreumaux P (2006) Impact of the mutation A21G (Flemish variant) on Alzheimer’s beta-amyloid dimers by molecular dynamics simulations. Biophys J 91:3829–3840

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Nguyen PH, Sterpone F, Campanera JM, Nasica-Labouze J, Derreumaux P (2016) Impact of the A2V mutation on the heterozygous and homozygous Aβ1-40 dimer structures from atomistic simulations. ACS Chem Neurosci 7:823–832

    CAS  PubMed  Google Scholar 

  98. Nguyen PH, Tarus B, Derreumaux P (2014) Familial Alzheimer A2 V mutation reduces the intrinsic disorder and completely changes the free energy landscape of the Aβ1-28 monomer. J Phys Chem B 118:501–510

    CAS  PubMed  Google Scholar 

  99. Nguyen PH, Sterpone F, Pouplana R, Derreumaux P, Campanera JM (2016) Dimerization mechanism of Alzheimer Aβ40 peptides: the high content of intrapeptide-stabilized conformations in A2V and A2T heterozygous dimers retards amyloid fibril formation. J Phys Chem B 120:12111–12126

    CAS  PubMed  Google Scholar 

  100. Das P, Chacko AR, Belfort G (2017) Alzheimer’s protective cross-interaction between wild-type and A2T variants alters Aβ42 dimer structure. ACS Chem Neurosci 8:606–618

    CAS  PubMed  Google Scholar 

  101. Li H, Nam Y, Salimi A, Lee JY (2020) Impact of A2V mutation and histidine tautomerism on Aβ42 monomer structures from atomistic simulations. J Chem Inf Model 60:3587–3592

    CAS  PubMed  Google Scholar 

  102. Aggarwal L, Biswas P (2020) Effect of Alzheimer’s disease causative and protective mutations on the hydration environment of amyloid-β. J Phys Chem B 124:2311–2322

    CAS  PubMed  Google Scholar 

  103. Banerjee S, Hashemi M, Lv Z, Maity S, Rochet JC, Lyubchenko YL (2017) A novel pathway for amyloids self-assembly in aggregates at nanomolar concentration mediated by the interaction with surfaces. Sci Rep 7:45592

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Alvarez AB, Caruso B, Rodríguez PEA, Petersen SB, Fidelio GD (2020) Aβ-amyloid fibrils are self-triggered by the interfacial lipid environment and low peptide content. Langmuir 36:8056–8065

    CAS  PubMed  Google Scholar 

  105. Farrugia MY, Caruana M, Ghio S, Camilleri A, Farrugia C, Cauchi RJ, Cappelli S, Chiti F, Vassallo N (2020) Toxic oligomers of the amyloidogenic HypF-N protein form pores in mitochondrial membranes. Sci Rep 10:17733

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Ghio S, Camilleri A, Caruana M, Ruf VC, Schmidt F, Leonov A, Ryazanov S, Griesinger C, Cauchi RJ, Kamp F et al (2019) Cardiolipin promotes pore-forming activity of alpha-synuclein oligomers in mitochondrial membranes. ACS Chem Neurosci 10:3815–3829

    CAS  PubMed  Google Scholar 

  107. Österlund N, Moons R, Ilag LL, Sobott F, Gräslund A (2019) Native ion mobility-mass spectrometry reveals the formation of β-barrel shaped amyloid-β hexamers in a membrane-mimicking environment. J Am Chem Soc 141:10440–10450

    PubMed  Google Scholar 

  108. Ait-Bouziad N, Lv G, Mahul-Mellier AL, Xiao S, Zorludemir G, Eliezer D, Walz T, Lashuel HA (2017) Discovery and characterization of stable and toxic Tau/phospholipid oligomeric complexes. Nat Commun 8:1678

    PubMed  PubMed Central  Google Scholar 

  109. Jang H, Arce FT, Ramachandran S, Kagan BL, Lal R, Nussinov R (2014) Disordered amyloidogenic peptides may insert into the membrane and assemble into common cyclic structural motifs. Chem Soc Rev 43:6750–6764

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Connelly L, Jang H, Arce FT, Capone R, Kotler SA, Ramachandran S, Kagan BL, Nussinov R, Lal R (2012) 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

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Serra-Batiste M, Ninot-Pedrosa M, Bayoumi M, Gairí M, Maglia G, Carulla N (2016) Aβ42 assembles into specific β-barrel pore-forming oligomers in membrane-mimicking environments. Proc Natl Acad Sci U S A 113:10866–10871

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Nguyen PH, Campanera JM, Ngo ST, Loquet A, Derreumaux P (2019) Tetrameric Aβ40 and Aβ42 β-barrel structures by extensive atomistic simulations. I. In a bilayer mimicking a neuronal membrane. J Phys Chem B 123:3643–3648

    CAS  PubMed  Google Scholar 

  113. Ngo ST, Nguyen PH, Derreumaux P (2020) Impact of A2T and D23N mutations on tetrameric Aβ42 barrel within a dipalmitoylphosphatidylcholine lipid bilayer membrane by replica exchange molecular dynamics. J Phys Chem B 124:1175–1182

    CAS  PubMed  Google Scholar 

  114. Di Scala C, Yahi N, Boutemeur S, Flores A, Rodriguez L, Chahinian H, Fantini J (2016) Common molecular mechanism of amyloid pore formation by Alzheimer’s β-amyloid peptide and α-synuclein. Sci Rep 6:28781

    PubMed  PubMed Central  Google Scholar 

  115. Ngo ST, Nguyen PH, Derreumaux P (2020) Stability of Aβ11-40 trimers with parallel and antiparallel β-sheet organizations in a membrane-mimicking environment by replica exchange molecular dynamics simulation. J Phys Chem B 124:617–626

    CAS  PubMed  Google Scholar 

  116. Ngo ST, Derreumaux P, Vu VV (2019) Probable transmembrane amyloid α-helix bundles capable of conducting Ca2+ ions. J Phys Chem B 123:2645–2653

    CAS  PubMed  Google Scholar 

  117. Sahoo A, Matysiak S (2019) Computational insights into lipid assisted peptide misfolding and aggregation in neurodegeneration. Phys Chem Chem Phys 21:22679–22694

    CAS  PubMed  Google Scholar 

  118. Lu Y, Shi XF, Nguyen PH, Sterpone F, Salsbury FR Jr, Derreumaux P (2019) Amyloid-β(29-42) dimeric conformations in membranes rich in omega-3 and omega-6 polyunsaturated fatty acids. J Phys Chem B 123:2687–2696

    CAS  PubMed  Google Scholar 

  119. Doig AJ, Derreumaux P (2015) Inhibition of protein aggregation and amyloid formation by small molecules. Curr Opin Struct Biol 30:50–56

    CAS  PubMed  Google Scholar 

  120. Chebaro Y, Derreumaux P (2009) Targeting the early steps of Abeta16-22 protofibril disassembly by N-methylated inhibitors: a numerical study. Proteins 75:442–452

    CAS  PubMed  Google Scholar 

  121. Chebaro Y, Jiang P, Zang T, Mu Y, Nguyen PH, Mousseau N, Derreumaux P (2012) Structures of Aβ17-42 trimers in isolation and with five small-molecule drugs using a hierarchical computational procedure. J Phys Chem B 116:8412–8422

    CAS  PubMed  Google Scholar 

  122. Zhang T, Zhang J, Derreumaux P, Mu Y (2013) Molecular mechanism of the inhibition of EGCG on the Alzheimer Aβ(1-42) dimer. J Phys Chem B 117:3993–4002

    CAS  PubMed  Google Scholar 

  123. Zhang T, Xu W, Mu Y, Derreumaux P (2014) Atomic and dynamic insights into the beneficial effect of the 1,4-naphthoquinon-2-yl-L-tryptophan inhibitor on Alzheimer’s Aβ1-42 dimer in terms of aggregation and toxicity. ACS Chem Neurosci 5:148–159

    PubMed  Google Scholar 

  124. Tarus B, Nguyen PH, Berthoumieu O, Faller P, Doig AJ, Derreumaux P (2015) Molecular structure of the NQTrp inhibitor with the Alzheimer Aβ1-28 monomer. Eur J Med Chem 91:43–50

    CAS  PubMed  Google Scholar 

  125. Berthoumieu O, Nguyen PH, Castillo-Frias MP, Ferre S, Tarus B, Nasica-Labouze J, Noël S, Saurel O, Rampon C, Doig AJ et al (2015) Combined experimental and simulation studies suggest a revised mode of action of the anti-Alzheimer disease drug NQ-Trp. Chemistry 21:12657–12666

    CAS  PubMed  Google Scholar 

  126. Minh Hung H, Nguyen MT, Tran PT, Truong VK, Chapman J, Quynh Anh LH, Derreumaux P, Vu VV, Ngo ST (2020) Impact of the astaxanthin, betanin, and EGCG compounds on small oligomers of amyloid Aβ40 peptide. J Chem Inf Model 60:1399–1408

    PubMed  Google Scholar 

  127. Nguyen PH, Del Castillo-Frias MP, Berthoumieux O, Faller P, Doig AJ, Derreumaux P (2018) Amyloid-β/drug interactions from computer simulations and cell-based assays. J Alzheimers Dis 64:S659–S672

    CAS  PubMed  Google Scholar 

  128. Liang C, Savinov SN, Fejzo J, Eyles SJ, Chen J (2019) Modulation of amyloid-β42 conformation by small molecules through nonspecific binding. J Chem Theory Comput 15:5169–5174

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Tran L (2018) Understanding the binding mechanism of amyloid-β inhibitors from molecular simulations. Curr Pharm Des 24:3341–3346

    CAS  PubMed  Google Scholar 

  130. Zhu M, De Simone A, Schenk D, Toth G, Dobson CM, Vendruscolo M (2013) Identification of small-molecule binding pockets in the soluble monomeric form of the Aβ42 peptide. J Chem Phys 139:035101

    PubMed  Google Scholar 

  131. Doig AJ, Del Castillo-Frias MP, Berthoumieu O, Tarus B, Nasica-Labouze J, Sterpone F, Nguyen PH, Hooper NM, Faller P, Derreumaux P (2017) Why is research on amyloid-β failing to give new drugs for Alzheimer’s disease? ACS Chem Neurosci 8:1435–1437

    CAS  PubMed  Google Scholar 

  132. Kim JE, Lee M (2003) Fullerene inhibits beta-amyloid peptide aggregation. Biochem Biophys Res Commun 303:576–579

    CAS  PubMed  Google Scholar 

  133. Linse S, Cabaleiro-Lago C, Xue WF, Lynch I, Lindman S, Thulin E, Radford SE, Dawson KA (2007) Nucleation of protein fibrillation by nanoparticles. Proc Natl Acad Sci U S A 104:8691–8696

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Fu Z, Luo Y, Derreumaux P, Wei G (2009) Induced beta-barrel formation of the Alzheimer’s Abeta25-35 oligomers on carbon nanotube surfaces: implication for amyloid fibril inhibition. Biophys J 97:1795–1803

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Li H, Luo Y, Derreumaux P, Wei G (2011) Carbon nanotube inhibits the formation of β-sheet-rich oligomers of the Alzheimer’s amyloid-β(16-22) peptide. Biophys J 101:2267–2276

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Limbocker R, Mannini B, Ruggeri FS, Cascella R, Xu CK, Perni M, Chia S, Chen SW, Habchi J, Bigi A et al (2020) Trodusquemine displaces protein misfolded oligomers from cell membranes and abrogates their cytotoxicity through a generic mechanism. Commun Biol 3:435

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Cox SJ, Lam B, Prasad A, Marietta HA, Stander NV, Joel JG, Sahoo BR, Guo F, Stoddard AK, Ivanova MI et al (2020) High-throughput screening at the membrane interface reveals inhibitors of amyloid-β. Biochemistry 59:2249–2258

    CAS  PubMed  Google Scholar 

  138. Man VH, Derreumaux P, Li MS, Roland C, Sagui C, Nguyen PH (2015) Picosecond dissociation of amyloid fibrils with infrared laser: a nonequilibrium simulation study. J Chem Phys 143:155101

    Google Scholar 

  139. Man VH, Derreumaux P, Nguyen PH (2016) Nonequilibrium all-atom molecular dynamics simulation of the bubble cavitation and application to dissociate amyloid fibrils. J Chem Phys 145:174113

    Google Scholar 

  140. Kawasaki T, Man VH, Sugimoto Y, Sugiyama N, Yamamoto H, Tsukiyama K, Wang J, Derreumaux P, Nguyen PH (2020) Infrared laser-induced amyloid fibril dissociation: a joint experimental/theoretical study on the GNNQQNY peptide. J Phys Chem B 124:6266–6277

    CAS  PubMed  Google Scholar 

  141. Man VH, Wang J, Derreumaux P, Nguyen PH (2021) Nonequilibrium Molecular Dynamics Simulations Of Infrared Laser-Induced Dissociation of a tetrameric Aβ42 β -barrel in a neuronal membrane model. Chem Phys Lipids 234:105030

    CAS  PubMed  Google Scholar 

  142. Derreumaux P (2001) Evidence that the 127-164 region of prion proteins has two equi-energetic conformations with beta or alpha features. Biophys J 81:1657–1665

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Santini S, Derreumaux P (2004) 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

    CAS  PubMed  Google Scholar 

  144. Santini S, Claude JB, Audic S, Derreumaux P (2003) Impact of the tail and mutations G131V and M129V on prion protein flexibility. Proteins 51:258–265

    CAS  PubMed  Google Scholar 

  145. De Simone A, Zagari A, Derreumaux P (2007) Structural and hydration properties of the partially unfolded states of the prion protein. Biophys J 93:1284–1292

    PubMed  PubMed Central  Google Scholar 

  146. Wille H, Dorosh L, Amidian S, Schmitt-Ulms G, Stepanova M (2019) Combining molecular dynamics simulations and experimental analyses in protein misfolding. Adv Protein Chem Struct Biol 118:33–110

    PubMed  Google Scholar 

  147. Peoc’h K, Levavasseur E, Delmont E, De Simone A, Laffont-Proust I, Privat N, Chebaro Y, Chapuis C, Bedoucha P, Brandel JP et al (2012) Substitutions at residue 211 in the prion protein drive a switch between CJD and GSS syndrome, a new mechanism governing inherited neurodegenerative disorders. Hum Mol Genet 21:5417–5428

    PubMed  Google Scholar 

  148. Chebaro Y, Derreumaux P (2009) The conversion of helix H2 to beta-sheet is accelerated in the monomer and dimer of the prion protein upon T183A mutation. J Phys Chem B 113:6942–6948

    CAS  PubMed  Google Scholar 

  149. Derreumaux P, Man VH, Wang J, Nguyen PH (2020) Tau R3-R4 domain dimer of the wild type and phosphorylated ser356 sequences. I. In solution by atomistic simulations. J Phys Chem B 124:2975–2983

    CAS  PubMed  Google Scholar 

  150. Haj-Yahya M, Gopinath P, Rajasekhar K, Mirbaha H, Diamond MI, Lashuel HA (2020) Site-specific hyperphosphorylation inhibits, rather than promotes, tau fibrillization, seeding capacity, and its microtubule binding. Angew Chem Int Ed Engl 59:4059–4067

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Maupetit J, Derreumaux P, Tuffery P (2009) PEP-FOLD: an online resource for de novo peptide structure prediction. Nucleic Acids Res 37:W498–W503

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Maupetit J, Derreumaux P, Tufféry P (2010) A fast method for large-scale de novo peptide and miniprotein structure prediction. J Comput Chem 31:726–738

    CAS  PubMed  Google Scholar 

  153. Thévenet P, Shen Y, Maupetit J, Guyon F, Derreumaux P, Tufféry P (2012) PEP-FOLD: an updated de novo structure prediction server for both linear and disulfide bonded cyclic peptides. Nucleic Acids Res 40:W288–W293

    PubMed  PubMed Central  Google Scholar 

  154. Shen Y, Maupetit J, Derreumaux P, Tufféry P (2014) Improved PEP-FOLD approach for peptide and miniprotein structure prediction. J Chem Theory Comput 10:4745–4758

    CAS  PubMed  Google Scholar 

  155. Sutherland GA, Grayson KJ, Adams NBP et al (2018) Probing the quality control mechanism of the Escherichia coli twin-arginine translocase with folding variants of a de novo-designed heme protein. J Biol Chem 293:6672–6681

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Lamiable A, Thévenet P, Rey J, Vavrusa M, Derreumaux P, Tufféry P (2016) PEP-FOLD3: faster de novo structure prediction for linear peptides in solution and in complex. Nucleic Acids Res 44:W449–W454

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Ngo ST, Nguyen PH, Derreumaux P (2021) Cholesterol molecules alter the energy landscape of small Aβ 1-42 oligomers. J Phys Chem B 125(9):2299–2307. https://doi.org/10.1021/acs.jpcb.1c00036

    Article  CAS  PubMed  Google Scholar 

  158. Ramamoorthy A, Sahoo BR, Zheng J, Chiricotto M, Straub JE, Dominguez L, Shea J-E, Dokholyan NV, De Simone A et al (2021) Amyloid oligomers: a joint experimental/computational perspective on Alzheimer’s disease, Parkinson’s disease, type II diabetes and amyotrophic lateral sclerosis. Chem Rev 121(4):2545–2647. https://doi.org/10.1021/acs.chemrev.0c01122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We acknowledge support by the “Initiative d’Excellence” program from the French State (Grant “DYNAMO”, ANR-11-LABX-0011-01, and “CACSICE”, ANR-11-EQPX-0008).

Notes

The authors declare no competing financial interest.

Author information

Authors and Affiliations

  1. Laboratoire de Biochimie Théorique, CNRS, Université de Paris, UPR 9080, Paris, France

    Phuong Hoang Nguyen & Philippe Derreumaux

  2. Institut de Biologie Physico-Chimique, Fondation Edmond de Rothschild, PSL Research University, Paris, France

    Phuong Hoang Nguyen & Philippe Derreumaux

  3. Université de Paris, BFA, UMR 8251, CNRS, ERL U1133, Inserm, RPBS, Paris, France

    Pierre Tufféry

Authors
  1. Phuong Hoang Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pierre Tufféry
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Philippe Derreumaux
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Philippe Derreumaux .

Editor information

Editors and Affiliations

  1. Lab de Biologie Structurale de la Cellule (CNRS UMR7654), Ecole Polytechnique, Palaiseau, France

    Thomas Simonson

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Nguyen, P.H., Tufféry, P., Derreumaux, P. (2022). Dynamics of Amyloid Formation from Simplified Representation to Atomistic Simulations. In: Simonson, T. (eds) Computational Peptide Science. Methods in Molecular Biology, vol 2405. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1855-4_5

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-1855-4_5

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-1854-7

  • Online ISBN: 978-1-0716-1855-4

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation