Wu Chun, Murray Megan M, Bernstein Summer L, Condron Margaret M, Bitan Gal, Shea Joan-Emma, Bowers Michael T
Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106-9501, USA.
J Mol Biol. 2009 Mar 27;387(2):492-501. doi: 10.1016/j.jmb.2009.01.029. Epub 2009 Jan 23.
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.
淀粉样β蛋白（Aβ）42的C末端在该蛋白的寡聚化过程中起重要作用，因此可能是治疗阿尔茨海默病的良好治疗靶点。已证实Aβ42的某些C末端片段（CTF）可破坏寡聚化并强烈抑制Aβ42诱导的神经毒性。在此，我们使用副本交换分子动力学模拟和离子淌度质谱研究了选定CTF [Aβ（x - 42）；x = 29 - 31，39]的结构。我们在显式溶剂中的模拟表明，CTF采用亚稳态β结构：Aβ（x - 42）（x = 29 - 31）为β发夹结构，Aβ（39 - 42）为延伸β链结构。当去除最后两个疏水残基时，Aβ（30 - 42）的β发夹结构转变为转角 - 螺旋构象，这表明I41和A42对于稳定Aβ42衍生的CTF中的β发夹结构至关重要。离子淌度质谱实验和无溶剂副本交换分子动力学模拟进一步突出了溶剂在确定CTF结构中的重要性。有溶剂结构和无溶剂结构之间的比较表明，疏水相互作用对于β发夹结构的形成至关重要。我们还讨论了CTF在破坏寡聚化过程中可能发挥的作用。
