The Structure of A beta 42 C-Terminal Fragments Probed by a Combined Experimental and Theoretical Study

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.