The Structure of Aβ42 C-Terminal Fragments Probed by a Combined Experimental and Theoretical Study

JOURNAL OF MOLECULAR BIOLOGY

卷:387

Article

Wu, Chun¹  Murray, Megan M.¹  Bernstein, Summer L.¹  Condron, Margaret M.²  Bitan, Gal^2,3,4  Shea, Joan-Emma^1,5  Bowers, Michael T.¹ 

[1] Univ Calif Santa Barbara, Dept Chem & Biochem, Santa Barbara, CA 93106 USA

[2] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA

[5] Univ Calif Santa Barbara, Dept Phys, Santa Barbara, CA 93106 USA

关键词: Alzheimer A beta 42 C-terminal fragments;    ion mobility;    molecular dynamics simulations;    beta-hairpin;   

DOI  :  10.1016/j.jmb.2009.01.029

来源: Elsevier

【 摘 要 】

The C-terminus of amyloid beta-protein (A beta) 42 plays an important role in this protein's oligomerization and may therefore be a good therapeutic target for the treatment of Alzheimer's disease. Certain C-terminal fragments (CTFs) of A beta 42 have been shown to disrupt oligomerization and to strongly inhibit A beta 42-induced neurotoxicity. Here we study the structures of selected CTFs [A beta(x-42); x = 29-31, 39] using replica exchange molecular dynamics simulations and ion mobility mass spectrometry. Our simulations in explicit solvent reveal that the CTFs adopt a metastable beta-structure: beta-hairpin for A beta(x-42) (x = 29-31) and extended beta-strand for A beta(39-42). The beta-hairpin of A beta(30-42) is converted into a turn-coil conformation when the last two hydrophobic residues are removed, suggesting that I41 and A42 are critical in stabilizing the beta-hairpin in A beta 42-derived CTFs. The importance of solvent in determining the structure of the CTFs is further highlighted in ion mobility mass spectrometry experiments and solvent-free replica exchange molecular dynamics simulations. A comparison between structures with solvent and structures without solvent reveals that hydrophobic interactions are critical for the formation of beta-hairpin. The possible role played by the CTFs in disrupting oligomerization is discussed. (C) 2009 Elsevier Ltd. All rights reserved.

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