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Study of the aggregation mechanism of polyglutamine peptides using replica exchange molecular dynamics simulations

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Abstract

Polyglutamine (polyQ, a peptide) with an abnormal repeat length is the causative agent of polyQ diseases, such as Huntington’s disease. Although glutamine is a polar residue, polyQ peptides form insoluble aggregates in water, and the mechanism for this aggregation is still unclear. To elucidate the detailed mechanism for the nucleation and aggregation of polyQ peptides, replica exchange molecular dynamics simulations were performed for monomers and dimers of polyQ peptides with several chain lengths. Furthermore, to determine how the aggregation mechanism of polyQ differs from those of other peptides, we compared the results for polyQ with those of polyasparagine and polyleucine. The energy barrier between the monomeric and dimeric states of polyQ was found to be relatively low, and it was observed that polyQ dimers strongly favor the formation of antiparallel β-sheet structures. We also found a characteristic behavior of the monomeric polyQ peptide: a turn at the eighth residue is always present, even when the chain length is varied. We previously showed that a structure including more than two sets of β-turns is stable, so a long monomeric polyQ chain can act as an aggregation nucleus by forming several pairs of antiparallel β-sheet structures within a single chain. Since the aggregation of polyQ peptides has some features in common with an amyloid fibril, our results shed light on the mechanism for the aggregation of polyQ peptides as well as the mechanism for the formation of general amyloid fibrils, which cause the onset of amyloid diseases.

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Abbreviations

Q:

Glutamine

polyQ:

Polyglutamine

MD:

Molecular dynamics

REMD:

Replica exchange molecular dynamics

MMD:

Multiple molecular dynamics

CD:

Circular dichroism

DPSS:

Dictionary of protein secondary structure

apβ:

Antiparallel β-sheet

pβ:

Parallel β-sheet

D min :

The minimum distance between the Cα atoms of the monomers (except for both termini)

Λ mono :

Distance from the Cα atom of the C-terminus to that of the N-terminus

\( n_{\mathrm{Hbond}}^{\mathrm{inter}} \) :

The number of intermolecular hydrogen bonds between two molecules

References

  1. The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983. doi:10.1016/0092-8674(93)90585-E

    Article  Google Scholar 

  2. Rubinsztein DC, Leggo J, Coles R, Almqvist E, Biancalana V, Cassiman JJ, Chotai K, Connarty M, Crauford D, Curtis A, Curtis D, Davidson MJ, Differ AM, Dode C, Dodge A, Frontali M, Ranen NG, Stine OC, Sherr M, Abbott MH, Franz ML, Graham CA, Harper PS, Hedreen JC, Jackson A, Kaplan JC, Losekoot M, MacMillan JC, Morrison P, Trottier Y, Novelletto A, Simpson SA, Theilmann J, Whittaker JL, Folstein SE, Ross CA, Hayden MR (1996) Phenotypic characterization of individuals with 30–40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36–39 repeats. Am J Hum Genet 59:16–22

    CAS  Google Scholar 

  3. Chen S, Ferrone FA, Wetzel R (2002) Huntington’s disease age-of-onset linked to polyglutamine aggregation nucleation. Proc Natl Acad Sci USA 99:11884–11889. doi:10.1073/pnas.182276099

    Article  CAS  Google Scholar 

  4. Cooper JK, Schilling G, Peters MF, Herring WJ, Sharp AH, Kaminsky Z, Masone J, Khan FA, Delanoy M, Borchelt DR, Dawson VL, Dawson TM, Ross CA (1998) Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture. Hum Mol Genet 7:783–790. doi:10.1093/hmg/7.5.783

    Article  CAS  Google Scholar 

  5. Chen S, Berthelier V, Hamilton JB, O’Nuallain B, Wetzel R (2002) Amyloid-like features of polyglutamine aggregates and their assembly kinetics. Biochemistry 41:7391–7399. doi:10.1021/bi011772q

    Article  CAS  Google Scholar 

  6. Scherzinger E, Lurz R, Turmaine M, Mangiarini L, Hollenbach B, Hasenbank R, Bates GP, Davies SW, Lehrach H, Wanker EE (1997) Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell 90:549–558. doi:10.1016/S0092-8674(00)80514-0

    Article  CAS  Google Scholar 

  7. Hollenbach B, Scherzinger E, Schweiger K, Lurz R, Lehrach H, Wanker EE (1999) Aggregation of truncated GST-HD exon 1 fusion proteins containing normal range and expanded glutamine repeats. Philos Trans R Soc Lond B Biol Sci 354:991–994

    Article  CAS  Google Scholar 

  8. Georgalis Y, Starikov EB, Hollenbach B, Lurz R, Scherzinger E, Saenger W, Lehrach H, Wanker EE (1998) Huntingtin aggregation monitored by dynamic light scattering. Proc Natl Acad Sci USA 95:6118–6121

    Article  CAS  Google Scholar 

  9. Scherzinger E, Sittler A, Schweiger K, Heiser V, Lurz R, Hasenbank R, Bates GP, Lehrach H, Wanker EE (1999) Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington’s disease pathology. Proc Natl Acad Sci USA 96:4604–4609. doi:10.1073/pnas.96.8.4604

    Article  CAS  Google Scholar 

  10. Perutz MF, Johnson T, Suzuki M, Finch JT (1994) Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc Natl Acad Sci USA 91:5355–5358

    Article  CAS  Google Scholar 

  11. Sharma D, Sharma S, Pasha S, Brahmachari SK (1999) Peptide models for inherited neurodegenerative disorders: conformation and aggregation properties of long polyglutamine peptides with and without interruptions. FEBS Lett 456:181–185. doi:10.1016/S0014-5793(99)00933-3

    Article  CAS  Google Scholar 

  12. Tanaka M, Morishima I, Akagi T, Hashikawa T, Nukina N (2001) Intra- and intermolecular beta-pleated sheet formation in glutamine-repeat inserted myoglobin as a model for polyglutamine diseases. J Biol Chem 276:45470–45475. doi:10.1074/jbc.M107502200

    Article  CAS  Google Scholar 

  13. Bevivino AE, Loll PJ (2001) An expanded glutamine repeat destabilizes native ataxin-3 structure and mediates formation of parallel beta-fibrils. Proc Natl Acad Sci USA 98:11955–11960. doi:10.1073/pnas.211305198

    Article  CAS  Google Scholar 

  14. Sharma D, Shinchuk LM, Inouye H, Wetzel R, Kirschner DA (2005) Polyglutamine homopolymers having 8–45 residues form slablike beta-crystallite assemblies. Proteins 61:398–411. doi:10.1002/prot.20602

    Article  CAS  Google Scholar 

  15. Vitalis A, Wang X, Pappu RV (2008) Atomistic simulations of the effects of polyglutamine chain length and solvent quality on conformational equilibria and spontaneous homodimerization. J Mol Biol 384:279–297. doi:10.1016/j.jmb.2008.09.026

    Article  CAS  Google Scholar 

  16. Crick SL, Jayaraman M, Frieden C, Wetzel R, Pappu RV (2006) Fluorescence correlation spectroscopy shows that monomeric polyglutamine molecules form collapsed structures in aqueous solutions. Proc Natl Acad Sci USA 103:16764–16769. doi:10.1073/pnas.0608175103

    Article  CAS  Google Scholar 

  17. Masino L, Kelly G, Leonard K, Trottier Y, Pastore A (2002) Solution structure of polyglutamine tracts in GST-polyglutamine fusion proteins. FEBS Lett 513:267–272. doi:10.1016/S0014-5793(02)02335-9

    Article  CAS  Google Scholar 

  18. Nakano M, Watanabe H, Rothstein SM, Tanaka S (2010) Comparative characterization of short monomeric polyglutamine peptides by replica exchange molecular dynamics simulation. J Phys Chem B 114:7056–7061. doi:10.1021/jp9122024

    Article  CAS  Google Scholar 

  19. Wang Y, Voth GA (2010) Molecular dynamics simulations of polyglutamine aggregation using solvent-free multiscale coarse-grained models. J Phys Chem B 114:8735–8743. doi:10.1021/jp1007768

    Article  CAS  Google Scholar 

  20. Laghaei R, Mousseau N (2010) Spontaneous formation of polyglutamine nanotubes with molecular dynamics simulations. J Chem Phys 132:165102. doi:10.1063/1.3383244

    Article  Google Scholar 

  21. Lakhani VV, Ding F, Dokholyan NV (2010) Polyglutamine induced misfolding of huntingtin exon1 is modulated by the flanking sequences. PLoS Comput Biol 6:e1000772. doi:10.1371/journal.pcbi.1000772

    Article  Google Scholar 

  22. Sugita Y, Okamoto Y (1999) Replica-exchange molecular dynamics method for protein folding. Chem Phys Lett 314:141–151. doi:10.1016/S0009-2614(99)01123-9

    Article  CAS  Google Scholar 

  23. Caves LS, Evanseck JD, Karplus M (1998) Locally accessible conformations of proteins: multiple molecular dynamics simulations of crambin. Protein Sci 7:649–666

    Article  CAS  Google Scholar 

  24. Straub JE, Rashkin AB, Thirumalai D (1994) Dynamics in rugged energy landscapes with applications to the S-peptide and ribonuclease A. J Am Chem Soc 116:2049–2063. doi:10.1021/ja00084a051

    Google Scholar 

  25. Elofsson A, Nilsson L (1993) How consistent are molecular dynamics simulations? Comparing structure and dynamics in reduced and oxidized Escherichia coli thioredoxin. J Mol Biol 233:766–780. doi:10.1006/jmbi.1993.1551

    Google Scholar 

  26. Case DA, Darden TA, Cheatham TE III, Simmerling CL, Wang J, Duke RE, Luo R, Crowley M, Walker RC, Zhang W, Merz KM, Wang B, Hayik S, Roitberg A, Seabra G, Kolossvary I, Wong KF, Paesani F, Vanicek J, Wu X, Brozell SR, Steinbrecher T, Gohlke H, Yang L, Tan C, Mongan J, Hornak V, Cui G, Mathews DH, Seetin MG, Sagui C, Babin V, Kollman PA (2008) AMBER 10. University of California San Francisco, San Francisco

    Google Scholar 

  27. 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. doi:10.1002/prot.20033

    Article  CAS  Google Scholar 

  28. Zhou R (2003) Free energy landscape of protein folding in water: explicit vs. implicit solvent. Proteins 53:148–161. doi:10.1002/prot.10483

    Article  CAS  Google Scholar 

  29. Shell MS, Ritterson R, Dill KA (2008) A test on peptide stability of AMBER force fields with implicit solvation. J Phys Chem B 112:6878–6886. doi:10.1021/jp800282x

    Article  CAS  Google Scholar 

  30. Gnanakaran S, Nymeyer H, Portman J, Sanbonmatsu KY, García AE (2003) Peptide folding simulations. Curr Opin Struct Biol 13:168–174. doi:10.1016/S0959-440X(03)00040-X

    Article  CAS  Google Scholar 

  31. Schneider T, Stoll E (1978) Molecular-dynamics study of a three-dimensional one-component model for distortive phase transitions. Phys Rev B 17:1302–1322. doi:10.1103/PhysRevB.17.1302

    Article  CAS  Google Scholar 

  32. Pastor RW, Brooks BR, Szabo A (1988) An analysis of the accuracy of Langevin and molecular dynamics algorithms. Mol Phys 65:1409–1419. doi:10.1080/00268978800101881

    Article  Google Scholar 

  33. Kabsch W, Sander C (1983) Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 22:2577–2637. doi:10.1002/bip.360221211

    Article  CAS  Google Scholar 

  34. Nakanishi K, Kikuchi M (2006) Thermodynamics of aggregation of two proteins. JPSJ 75:64803–64806. doi:10.1143/JPSJ.75.064803

    Article  Google Scholar 

  35. Nagai Y, Inui T, Popiel HA, Fujikake N, Hasegawa K, Urade Y, Goto Y, Naiki H, Toda T (2007) A toxic monomeric conformer of the polyglutamine protein. Nat Struct Mol Biol 14:332–340. doi:10.1038/nsmb1215

    Article  CAS  Google Scholar 

  36. Thakur AK, Wetzel R (2002) Mutational analysis of the structural organization of polyglutamine aggregates. Proc Natl Acad Sci USA 99:17014–17019. doi:10.1073/pnas.252523899

    Article  CAS  Google Scholar 

  37. Nakano M (2010) Doctoral thesis. Kobe University, Kobe Japan

  38. DeLano Scientific LLC (2006) PyMOL viewer v0.99. DeLano Scientific LLC, Palo Alto

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Acknowledgments

We thank Dr. Takatoshi Fujita for useful comments and discussions. The numerical calculations were partially carried out on a PC-cluster system in the Cybermedia Center at Osaka University.

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Authors and Affiliations

  1. Graduate School of Human Development and Environment, Kobe University, 3-11, Tsurukabuto, Nada, Kobe, 657-8501, Japan

    Miki Nakano & Kuniyoshi Ebina

  2. Graduate School of System Informatics, Department of Computational Science, Kobe University, 1-1, Rokkodai, Nada, Kobe, 657-8501, Japan

    Shigenori Tanaka

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  1. Miki Nakano
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Correspondence to Miki Nakano or Shigenori Tanaka.

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Nakano, M., Ebina, K. & Tanaka, S. Study of the aggregation mechanism of polyglutamine peptides using replica exchange molecular dynamics simulations. J Mol Model 19, 1627–1639 (2013). https://doi.org/10.1007/s00894-012-1712-9

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