Jang Hyunbum, Zheng Jie, Lal Ratnesh, Nussinov Ruth
Center for Cancer Research Nanobiology Program, SAIC-Frederick Inc. NCI-Frederick, Frederick, MD 21702, USA.
Trends Biochem Sci. 2008 Feb;33(2):91-100. doi: 10.1016/j.tibs.2007.10.007. Epub 2008 Jan 7.
The mechanism of amyloid toxicity is poorly understood and there are two schools of thought in this hotly debated field: the first favors membrane destabilization by intermediate-to-large amyloid oligomers, with consequent thinning and non-specific ion leakage; the second favors ion-specific permeable channels lined by small amyloid oligomers. Published results currently support both mechanisms. However, the amyloidbeta (Abeta) peptide has recently been shown to form a U-shaped 'beta-strand-turn-beta-strand' structure. This structure and the available physiological data present a challenge for computational biology--to provide candidate models consistent with the experimental data. Modeling based on small Abeta oligomers containing extramembranous N-termini predicts channels with shapes and dimensions consistent with experimentally derived channel structures. These results support the hypothesis that small Abeta oligomers can form ion channels. Molecular dynamics modeling can provide blueprints of 3D structural conformations for many other amyloids whose membrane association is key to their toxicity.
淀粉样蛋白毒性的机制尚不清楚，在这个激烈争论的领域中有两种观点：第一种观点认为，中等大小到大型的淀粉样蛋白寡聚体使膜不稳定，导致膜变薄和非特异性离子泄漏；第二种观点认为，由小淀粉样蛋白寡聚体排列形成离子特异性通透通道。目前已发表的结果支持这两种机制。然而，最近有研究表明，淀粉样β（Aβ）肽能形成一种U形的“β-链-转角-β-链”结构。这种结构和现有的生理数据给计算生物学带来了挑战——要提供与实验数据一致的候选模型。基于含有膜外N端的小Aβ寡聚体进行建模，预测出的通道形状和尺寸与实验得出的通道结构一致。这些结果支持了小Aβ寡聚体能形成离子通道的假说。分子动力学建模可以为许多其他淀粉样蛋白提供三维结构构象蓝图，这些淀粉样蛋白与膜的结合是其毒性的关键。
