Jang Hyunbum, Connelly Laura, Arce Fernando Teran, Ramachandran Srinivasan, Kagan Bruce L, Lal Ratnesh, Nussinov Ruth
Basic Science Program, SAIC-Frederick, Inc., Center for Cancer Research Nanobiology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
J Chem Theory Comput. 2013 Jan 8;9(1):822-833. doi: 10.1021/ct300916f. Epub 2012 Dec 5.
Amyloid-β (Aβ) oligomers destabilize cellular ionic homeostasis, mediating Alzheimer's disease (AD). It is still unclear whether the mechanism (i) is mediated by cell surface receptors; (ii) is direct, with Aβ oligomers interacting with membrane lipids; or (iii) both mechanisms take place. Recent studies indicate that Aβ oligomers may act by either of the last two. Little is known about the oligomers' structures and how they spontaneously insert into the membrane. Using explicit solvent molecular dynamics (MD) simulations, we show that fibril-like Aβ(17-42) (p3) oligomer is capable of penetrating the membrane. Insertion is similar to that observed for protegrin-1 (PG-1), a cytolytic β-sheet-rich antimicrobial peptide (AMP). Both Aβ and PG-1 favor the amphipathic interface of the lipid bilayer in the early stage of interaction with the membrane. U-shaped Aβ 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 Aβ 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 β-hairpin state, and may (or may not) convert to a U-shape in the bilayer. Together with earlier observations, our results point to a non-specific, broadly heterogeneous landscape of membrane-inserting oligomer conformations, pathways, and membrane-mediated toxicity of β-rich oligomers.
淀粉样β蛋白（Aβ）寡聚体破坏细胞离子稳态，介导阿尔茨海默病（AD）。目前尚不清楚其机制：（i）是否由细胞表面受体介导；（ii）是否是直接的，即Aβ寡聚体与膜脂相互作用；或者（iii）这两种机制是否都发生。最近的研究表明，Aβ寡聚体可能通过后两种机制中的任何一种起作用。关于寡聚体的结构以及它们如何自发插入膜中，人们知之甚少。使用显式溶剂分子动力学（MD）模拟，我们表明纤维样Aβ(17 - 42)（p3）寡聚体能够穿透膜。其插入过程与防御素-1（PG-1）类似，PG-1是一种富含β折叠的溶细胞性抗菌肽（AMP）。在与膜相互作用的早期阶段，Aβ和PG-1都倾向于脂质双层的两亲性界面。在溶液和膜中都观察到了U形Aβ寡聚体，这表明预形成的种子可以在淀粉样纤维的生长阶段和膜毒性中共享。在这里，我们提供了Aβ寡聚体可能的膜插入途径中的连续事件。我们推测，对于U形基序，三聚体是有效插入的最小寡聚体尺寸。我们提出，单体和二聚体可能以（显然是在途径上的）聚集中间态β发夹状态插入，并可能（或可能不）在双层中转变为U形。与早期观察结果一起，我们的结果表明，富含β折叠的寡聚体在膜插入构象、途径和膜介导毒性方面存在非特异性、广泛的异质性。
