Jang Hyunbum, Zheng Jie, Nussinov Ruth
Center for Cancer Research Nanobiology Program, SAIC-Frederick, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
Biophys J. 2007 Sep 15;93(6):1938-49. doi: 10.1529/biophysj.107.110148. Epub 2007 May 25.
Here we model the Alzheimer beta-peptide ion channel with the goal of obtaining insight into the mechanism of amyloid toxicity. The models are built based on NMR data of the oligomers, with the universal U-shaped (strand-turn-strand) motif. After 30-ns simulations in the bilayer, the channel dimensions, shapes and subunit organization are in good agreement with atomic force microscopy (AFM). The models use the Abeta(17-42) pentamer NMR-based coordinates. Extension and bending of the straight oligomers lead to two channel topologies, depending on the direction of the curvature: 1), the polar/charged N-terminal beta-strand of Abeta(17-42) faces the water-filled pore, and the hydrophobic C-terminal beta-strand faces the bilayer (CNpNC; p for pore); and 2), the C-terminal beta-strand faces the solvated pore (NCpCN). In the atomistic simulations in a fully solvated DOPC lipid bilayer, the first (CNpNC) channel preserves the pore and conducts solvent; by contrast, hydrophobic collapse blocks the NCpCN channel. AFM demonstrated open pores and collapsed complexes. The final averaged CNpNC pore dimensions (outer diameter 8 nm; inner diameter approximately 2.5 nm) are in the AFM range (8-12 nm; approximately 2 nm, respectively). Further, in agreement with high-resolution AFM images, during the simulations, the channels spontaneously break into ordered subunits in the bilayer; however, we also observe that the subunits are loosely connected by partially disordered inner beta-sheet, suggesting subunit mobility in the bilayer. The cationic channel has strong selective affinity for Ca(2+), supporting experimental calcium-selective beta-amyloid channels. Membrane permeability and consequent disruption of calcium homeostasis were implicated in cellular degeneration. Consequently, the CNpNC channel topology can sign cell death, offering insight into amyloid toxicity via an ion "trap-release" transport mechanism. The observed loosely connected subunit organization suggests that amyloid channel formation in the bilayer is a dynamic, fluid process involving subunit association, dissociation, and channel rearrangements.
在此，我们构建阿尔茨海默β-肽离子通道模型，旨在深入了解淀粉样蛋白毒性机制。这些模型基于具有通用U形（链-转角-链）基序的寡聚体的核磁共振数据构建。在双层膜中进行30纳秒的模拟后，通道尺寸、形状和亚基组织与原子力显微镜（AFM）结果高度吻合。这些模型使用基于Abeta(17 - 42)五聚体核磁共振的坐标。直链寡聚体的延伸和弯曲会导致两种通道拓扑结构，这取决于曲率方向：1）Abeta(17 - 42)的极性/带电荷的N端β链面向充满水的孔，疏水的C端β链面向双层膜（CNpNC；p代表孔）；2）C端β链面向溶剂化孔（NCpCN）。在完全溶剂化的二油酰磷脂酰胆碱（DOPC）脂质双层的原子模拟中，第一个（CNpNC）通道保持孔道并传导溶剂；相比之下，疏水塌陷会阻塞NCpCN通道。原子力显微镜显示存在开放孔道和塌陷复合物。最终平均的CNpNC孔道尺寸（外径8纳米；内径约2.5纳米）在原子力显微镜测量范围内（分别为8 - 12纳米；约2纳米）。此外，与高分辨率原子力显微镜图像一致，在模拟过程中，通道在双层膜中自发分解为有序的亚基；然而，我们也观察到亚基通过部分无序的内部β折叠松散连接在一起，表示双层膜中亚基具有流动性。阳离子通道对Ca(2+)具有很强的选择性亲和力，支持实验中钙选择性β-淀粉样蛋白通道的存在。膜通透性以及随之而来的钙稳态破坏与细胞变性有关。因此，CNpNC通道拓扑结构可能标志着细胞死亡，通过离子“捕获-释放”转运机制为淀粉样蛋白毒性提供了深入见解。观察到的松散连接的亚基组织表明，双层膜中淀粉样蛋白通道的形成是一个动态、流动的过程，涉及亚基的缔合、解离和通道重排。
