title: Stable polyglutamine dimers can contain β-hairpins with interdigitated side chains-but not α-helices, β-nanotubes, β-pseudohelices, or steric zippers.
abstract: A common thread connecting nine fatal neurodegenerative protein aggregation diseases is an abnormally expanded polyglutamine tract found in the respective proteins. Although the structure of this tract in the large mature aggregates is increasingly well described, its structure in the small early aggregates remains largely unknown. As experimental evidence suggests that the most toxic species along the aggregation pathway are the small early ones, developing strategies to alleviate disease pathology calls for understanding the structure of polyglutamine peptides in the early stages of aggregation. Here, we present a criterion, grounded in available experimental data, that allows for using kinetic stability of dimers to assess whether a given polyglutamine conformer can be on the aggregation path. We then demonstrate that this criterion can be assessed using present-day molecular dynamics simulations. We find that although the α-helical conformer of polyglutamine is very stable, dimers of α-helices lack the kinetic stability necessary to support further oligomerization. Dimers of steric zipper, β-nanotube, and β-pseudohelix conformers are also too short-lived to initiate aggregation. The β-hairpin-containing conformers, instead, invariably form very stable dimers when their side chains are interdigitated. Combining these findings with the implications of recent solid-state NMR data on mature fibrils, we propose a possible pathway for the initial stages of polyglutamine aggregation, in which β-hairpin-containing conformers act as templates for fibril formation.
authors.affiliation: Fachbereich Physik, Freie Universität Berlin, Berlin, Germany; Institute of Biochemistry and Biology, University of Potsdam, Potsdam, Germany. Electronic address: markus.miettinen@iki.fi.
authors.forename: Markus S
authors.initials: MS
authors.lastname: Miettinen
authors.affiliation: Institut National de la santé et de la recherche medicale, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Institut National de la Transfusion Sanguine, Paris, France.
authors.forename: Luca
authors.initials: L
authors.lastname: Monticelli
authors.affiliation: Department of Applied Physics, Aalto University School of Science, Espoo, Finland.
authors.forename: Praveen
authors.initials: P
authors.lastname: Nedumpully-Govindan
authors.affiliation: Department of Theory and Bio-Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Knecht
authors.affiliation: Institute of Biochemistry and Biology, University of Potsdam, Potsdam, Germany. Electronic address: ignatova@uni-potsdam.de.
authors.forename: Zoya
authors.initials: Z
authors.lastname: Ignatova
mesh_terms: D019281:Dimerization; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D043942:Nanotubes / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D058105:Polymerization; D066329:Protein Aggregates; D017433:Protein Structure, Secondary
chemical_list: D010455:Peptides; D066329:Protein Aggregates; C097188:polyglutamine
references.citation: Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11884-9
references.pmid: 12186976
references.citation: Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4604-9
references.pmid: 10200309
references.citation: J Chem Theory Comput. 2012 Aug 14;8(8):2725-2740
references.pmid: 22904695
references.citation: Brain Pathol. 2006 Jul;16(3):218-27
references.pmid: 16911479
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5591-5
references.pmid: 11960014
references.citation: Nat Chem Biol. 2011 Oct 30;7(12):925-34
references.pmid: 22037470
references.citation: Physiol Rev. 2010 Jul;90(3):905-81
references.pmid: 20664076
references.citation: Cell. 1997 Aug 8;90(3):549-58
references.pmid: 9267034
references.citation: Cell. 1998 Oct 2;95(1):41-53
references.pmid: 9778246
references.citation: J Chem Phys. 2007 Jan 7;126(1):014101
references.pmid: 17212484
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16764-9
references.pmid: 17075061
references.citation: J Neurochem. 2009 Sep;110(6):1737-65
references.pmid: 19650870
references.citation: J Chem Theory Comput. 2008 Mar;4(3):435-47
references.pmid: 26620784
references.citation: J Phys Chem B. 2012 Aug 30;116(34):10259-65
references.pmid: 22770401
references.citation: Biophys J. 2008 May 15;94(10):4031-40
references.pmid: 18234827
references.citation: PLoS One. 2012;7(2):e32131
references.pmid: 22384157
references.citation: Nature. 1982 Mar 18;296(5854):266-7
references.pmid: 7199623
references.citation: J Comput Chem. 1999 Jun;20(8):786-798
references.pmid: 35619462
references.citation: Nat Rev Mol Cell Biol. 2005 Nov;6(11):891-8
references.pmid: 16167052
references.citation: J Mol Biol. 2012 Aug 24;421(4-5):466-90
references.pmid: 22306404
references.citation: Cell. 1998 Oct 2;95(1):55-66
references.pmid: 9778247
references.citation: J Pept Res. 1997 Jul;50(1):73-5
references.pmid: 9273890
references.citation: Proc Natl Acad Sci U S A. 2004 May 25;101(21):7885-90
references.pmid: 15143215
references.citation: J Mol Graph. 1996 Feb;14(1):33-8, 27-8
references.pmid: 8744570
references.citation: J Comput Chem. 2004 Aug;25(11):1400-15
references.pmid: 15185334
references.citation: Biophys J. 1980 Oct;32(1):361-80
references.pmid: 7248455
references.citation: Brain Res Bull. 2001 Oct-Nov 1;56(3-4):349-52
references.pmid: 11719271
references.citation: J Phys Chem B. 2012 Oct 11;116(40):12168-79
references.pmid: 22978784
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15400-5
references.pmid: 16230628
references.citation: Biophys J. 2010 Jul 21;99(2):647-55
references.pmid: 20643085
references.citation: Hum Mol Genet. 2008 Feb 1;17(3):345-56
references.pmid: 17947294
references.citation: J Biol Chem. 2012 Jan 13;287(3):2068-78
references.pmid: 22134925
references.citation: Nat Chem Biol. 2010 Jan;6(1):7-8
references.pmid: 20016493
references.citation: Nat Struct Mol Biol. 2007 Apr;14(4):332-40
references.pmid: 17369839
references.citation: J Comput Chem. 2009 Dec;30(16):2785-91
references.pmid: 19399780
references.citation: Hum Mol Genet. 2005 Mar 15;14(6):765-74
references.pmid: 15689354
references.citation: Annu Rev Neurosci. 2007;30:575-621
references.pmid: 17417937
references.citation: Proteins. 2005 Nov 1;61(2):398-411
references.pmid: 16114051
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):11955-60
references.pmid: 11572942
references.citation: Nat Struct Mol Biol. 2011 Mar;18(3):328-36
references.pmid: 21317897
references.citation: Biochemistry. 2002 Jun 11;41(23):7391-9
references.pmid: 12044172
references.citation: Nature. 2004 Oct 14;431(7010):805-10
references.pmid: 15483602
references.citation: J Neurosci. 2010 Aug 4;30(31):10541-50
references.pmid: 20685997
references.citation: J Mol Biol. 2001 Aug 3;311(1):173-82
references.pmid: 11469866
references.citation: PLoS Biol. 2004 Oct;2(10):e321
references.pmid: 15383837
references.citation: Neuron. 2002 Jun 13;34(6):905-19
references.pmid: 12086639
references.citation: Cell. 2010 Dec 23;143(7):1121-35
references.pmid: 21183075
references.citation: Acc Chem Res. 2006 Sep;39(9):671-9
references.pmid: 16981684
references.citation: J Biol Chem. 2007 Feb 2;282(5):3157-64
references.pmid: 17121819
references.citation: PLoS Comput Biol. 2005 Aug;1(3):230-5
references.pmid: 16158094
references.citation: J Chem Theory Comput. 2008 Jan;4(1):116-22
references.pmid: 26619985
references.citation: J Biol Chem. 2011 Mar 11;286(10):8188-8196
references.pmid: 21209075
references.citation: J Phys Chem B. 2010 May 27;114(20):7056-61
references.pmid: 20441177
references.citation: J Mol Biol. 2011 Sep 9;412(1):121-36
references.pmid: 21763317
references.citation: Acta Neuropathol. 2010 Oct;120(4):419-37
references.pmid: 20514488
references.citation: Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5355-8
references.pmid: 8202492
references.citation: Hum Mol Genet. 2005 Mar 1;14(5):679-91
references.pmid: 15661755
references.citation: J Mol Biol. 2012 Aug 10;421(2-3):160-71
references.pmid: 22406275
references.citation: J Phys Chem B. 2008 Dec 25;112(51):16843-50
references.pmid: 19367817
references.citation: FASEB J. 2010 May;24(5):1311-9
references.pmid: 20032312
references.citation: J Mol Biol. 2006 Apr 21;358(1):330-45
references.pmid: 16503338
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11402-7
references.pmid: 16076956
references.citation: J Chem Theory Comput. 2010 Feb 9;6(2):459-66
references.pmid: 26617301
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):17014-9
references.pmid: 12444250
references.citation: J Mol Biol. 2012 Aug 24;421(4-5):587-600
references.pmid: 22306738
references.citation: Anal Biochem. 2001 Aug 15;295(2):227-36
references.pmid: 11488626
references.citation: Nature. 2003 Jan 23;421(6921):373-9
references.pmid: 12540902
references.citation: Nature. 2000 Jul 13;406(6792):195-9
references.pmid: 10910361
references.citation: J Mol Biol. 2013 Apr 12;425(7):1183-97
references.pmid: 23353826
references.citation: Biomacromolecules. 2005 Jan-Feb;6(1):425-32
references.pmid: 15638548
references.citation: Nat Chem Biol. 2006 Jun;2(6):319-23
references.pmid: 16699519