Mechanisms for the Insertion of Toxic, Fibril-like 尾-Amyloid Oligomers into the Membrane

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• 作者：Hyunbum Jang ; Laura Connelly ; Fernando Teran Arce ; Srinivasan Ramachandran ; Bruce L. Kagan ; Ratnesh Lal ; Ruth Nussinov
• 刊名：Journal of Chemical Theory and Computation
• 出版年：2013
• 出版时间：January 8, 2013
• 年：2013
• 卷：9
• 期：1
• 页码：822-833
• 全文大小：741K
• 年卷期：v.9,no.1(January 8, 2013)
• ISSN：1549-9626

文摘

Amyloid-尾 (A尾) oligomers destabilize cellular ionic homeostasis, mediating Alzheimer鈥檚 disease (AD). It is still unclear whether the mechanism (i) is mediated by cell surface receptors; (ii) is direct, with A尾 oligomers interacting with membrane lipids; or (iii) both mechanisms take place. Recent studies indicate that A尾 oligomers may act by either of the last two. Little is known about the oligomers鈥?structures and how they spontaneously insert into the membrane. Using explicit solvent molecular dynamics (MD) simulations, we show that fibril-like A尾_17鈥?2 (p3) oligomer is capable of penetrating the membrane. Insertion is similar to that observed for protegrin-1 (PG-1), a cytolytic 尾-sheet-rich antimicrobial peptide (AMP). Both A尾 and PG-1 favor the amphipathic interface of the lipid bilayer in the early stage of interaction with the membrane. U-shaped A尾 oligomers are observed in solution and in the membrane, suggesting that the preformed seeds can be shared by amyloid fibrils in the growth phase and membrane toxicity. Here we provide sequential events in possible A尾 oligomer membrane-insertion pathways. We speculate that for the U-shaped motif, a trimer is the minimal oligomer size to insert effectively. We propose that monomers and dimers may insert in (apparently on-pathway) aggregation-intermediate 尾-hairpin state and may (or may not) convert to a U-shape in the bilayer. Together with earlier observations, our results point to a nonspecific, broadly heterogeneous landscape of membrane-inserting oligomer conformations, pathways, and membrane-mediated toxicity of 尾-rich oligomers.