title: Discriminating early stage A{beta}42 monomer structures using chirality-induced 2DIR spectroscopy in a simulation study.
abstract: Elucidating the structural features of the Abeta monomer, the peptide constituent of amyloid fibrils found in Alzheimer's disease, can enable a direct characterization of aggregation pathways. Recent studies support the view that the ensemble of Abeta42 monomers is a mixture of diverse ordered and disordered conformational species, which can be classified according to the formation of a characteristic beta-hairpin conformation in a certain region. Despite the disparity in the structural features of these species, commonly used spectroscopic techniques such as NMR may not directly trace the conformational dynamics in the ensemble due to the limited time resolution and the lack of well-resolved spectral features for different comformers. Here we use molecular dynamics simulations combined with simulations of two-dimensional IR (2DIR) spectra to investigate the structure of these species, their interchange kinetics, and their spectral features. We show that while the discrimination efficiency of the ordinary, nonchiral 2DIR signal is limited due to its intrinsic dependence on common order parameters that are dominated by the generally unstructured part of the sequence, signals with carefully designed chirality-sensitive pulse configurations have the high resolution required for differentiating the various monomer structures. Our combined simulation studies indicate the power of the chirality-induced (CI) 2DIR technique in investigating early events in Abeta42 aggregation and open the possibility for their use as a novel experimental tool.
authors.affiliation: Dalian Institute of Chemical Physics, Liaoning, China. wzhuang@dicp.ac.cn
authors.forename: Wei
authors.initials: W
authors.lastname: Zhuang
authors.forename: Nikolaos G
authors.initials: NG
authors.lastname: Sgourakis
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Li
authors.forename: Angel E
authors.initials: AE
authors.lastname: Garcia
authors.forename: Shaul
authors.initials: S
authors.lastname: Mukamel
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation; D013055:Spectrophotometry, Infrared / Q000379:methods*; D013237:Stereoisomerism
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16742-7
references.pmid: 12481027
references.citation: J Mol Biol. 1992 Jun 20;225(4):1075-93
references.pmid: 1613791
references.citation: Nature. 1987 Feb 19-25;325(6106):733-6
references.pmid: 2881207
references.citation: Science. 2006 Sep 29;313(5795):1951-5
references.pmid: 17008529
references.citation: Biochemistry. 2006 Mar 7;45(9):2810-9
references.pmid: 16503636
references.citation: Protein Sci. 2006 Mar;15(3):420-8
references.pmid: 16501222
references.citation: J Am Chem Soc. 2004 Feb 25;126(7):1992-2005
references.pmid: 14971932
references.citation: Nature. 2006 Nov 23;444(7118):469-72
references.pmid: 17122853
references.citation: Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4074-8
references.pmid: 16537487
references.citation: J Phys Chem B. 2009 Sep 3;113(35):12037-49
references.pmid: 19496555
references.citation: Annu Rev Phys Chem. 1997;48:357-86
references.pmid: 9348659
references.citation: Nature. 2005 Mar 31;434(7033):625-8
references.pmid: 15800619
references.citation: J Comput Chem. 2005 Dec;26(16):1701-18
references.pmid: 16211538
references.citation: Nat Rev Neurosci. 2003 Jan;4(1):49-60
references.pmid: 12511861
references.citation: J Mol Biol. 2006 Dec 15;364(5):853-62
references.pmid: 17046788
references.citation: Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):330-5
references.pmid: 12506200
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11185-90
references.pmid: 16040800
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14233-6
references.pmid: 17675411
references.citation: Science. 2002 Jul 19;297(5580):353-6
references.pmid: 12130773
references.citation: Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7720-5
references.pmid: 18499799
references.citation: Eur J Biochem. 2001 Nov;268(22):5930-6
references.pmid: 11722581
references.citation: Science. 1991 Dec 13;254(5038):1598-603
references.pmid: 1749933
references.citation: Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17342-7
references.pmid: 16293696
references.citation: J Phys Chem B. 2006 Feb 23;110(7):3362-74
references.pmid: 16494351
references.citation: Biophys J. 2001 Jan;80(1):31-44
references.pmid: 11159381
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6614-9
references.pmid: 19346479
references.citation: Nature. 2005 Mar 10;434(7030):199-202
references.pmid: 15758995
references.citation: J Phys Chem B. 2008 May 15;112(19):5930-7
references.pmid: 18078331
references.citation: Angew Chem Int Ed Engl. 2009;48(21):3750-81
references.pmid: 19415637
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17751-6
references.pmid: 19815514
references.citation: FEBS J. 2005 Aug;272(15):3938-49
references.pmid: 16045764
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):18934-8
references.pmid: 17146054
references.citation: Acc Chem Res. 2008 Mar;41(3):432-41
references.pmid: 18288813
references.citation: J Struct Biol. 2000 Jun;130(2-3):130-41
references.pmid: 10940221
references.citation: J Mol Biol. 2007 May 18;368(5):1448-57
references.pmid: 17397862