The structure of Abeta42 C-terminal fragments probed by a combined experimental and theoretical study.
The C-terminus of amyloid beta-protein (Abeta) 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 Abeta42 have been shown to disrupt oligomerization and to strongly inhibit Abeta42-induced neurotoxicity. Here we study the structures of selected CTFs [Abeta(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 Abeta(x-42) (x=29-31) and extended beta-strand for Abeta(39-42). The beta-hairpin of Abeta(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 Abeta42-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.
Wu
Chun
C
Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106-9501, USA.
Murray
Megan M
MM
Bernstein
Summer L
SL
Condron
Margaret M
MM
Bitan
Gal
G
Shea
Joan-Emma
JE
Bowers
Michael T
MT
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D007477:Ions; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D012995:Solubility
D016229:Amyloid beta-Peptides; D007477:Ions