The α-to-β conformational transition of Alzheimer's Aβ-(1-42) peptide in aqueous media is reversible:: A step by step conformational analysis suggests the location of β conformation seeding
The α-to-β conformational transition of Alzheimer's Aβ-(1-42) peptide in aqueous media is reversible:: A step by step conformational analysis suggests the location of β conformation seeding
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DOI：
10.1002/cbic.200500223
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发表时间：
2006-02-01
期刊：
影响因子：
3.2
通讯作者：
Picone, D
中科院分区：
文献类型：
--
作者：
Tomaselli, S;Esposito, V;Picone, D
目前关于β -淀粉样蛋白（A β）肽原纤维的作用的观点包括将其视为阿尔茨海默病病理的原因或具有保护功能。在过去的几年里，也有人认为可溶性低聚物可能是最重要的有毒物质。在所有情况下，对可溶性A β肽构象性质的研究构成了设计具有“抗淀粉样蛋白”活性的分子的基本方法。我们通过实验研究了A β -(1-42)肽从嵌入在膜中的α螺旋状态到淀粉样原纤维中以β片结构为特征的最终状态的构象路径。利用CD谱和核磁共振谱在不同极性介质中监测构象步骤。这是通过改变水和六氟异丙醇（HFIP）的组成来实现的。在HFIP存在的情况下，可以在含水量非常高（高达999,6水；v/v）的溶液中观察到β构象。只要加入适量的HFIP，这些螺旋就可以变回α螺旋。当水的含量大于80% （v/v）时，A β -(1-42)从α构象转变为β构象。在高含水量的HFIP/H2O中求解的核磁共振结构表明，从极极性环境到极极性环境，长n端螺旋基本保留，而短c端螺旋丢失。借助显式溶剂中的分子动力学模拟，详细研究了完整的构象路径，这导致了可能产生β构象的残基的定位。所获得的结构可能有助于发现体内受环境条件影响更大的区域。这反过来又有助于设计能够抑制纤维沉积或恢复寡聚化过程的分子。
Current views of the role of beta-amyloid (A beta) peptide fibrils range from regarding them as the cause of Alzheimer's pathology to having a protective function. In the last few years, it has also been suggested that soluble oligomers might be the most important toxic species. In all cases, the study of the conformational properties of A beta peptides in soluble form constitutes a basic approach to the design of molecules with "antiamyloid" activity. We have experimentally investigated the conformational path that can lead the A beta-(1-42) peptide from the native state, which is represented by an alpha helix embedded in the membrane, to the final state in the amyloid fibrils, which is characterized by beta-sheet structures. The conformational steps were monitored by using CD and NMR spectroscopy in media of varying polarities. This was achieved by changing the composition of water and hexafluoroisopropanol (HFIP). In the presence of HFIP beta conformations can be observed in solutions that have very high water content (up to 999,6 water; v/v). These can be turned back to alpha helices simply by adding the appropriate amount of HFIP. The transition of A beta-(1-42) from alpha to beta conformations occurs when the amount of water is higher than 80% (v/v). The NMR structure solved in HFIP/H2O with high water content showed that on going from very apolar to polar environments, the long N-terminal helix is essentially retained, whereas the shorter C-terminal helix is lost. The complete conformational path was investigated in detail with the aid of molecular-dynamics simulations in explicit solvent, which led to the localization of residues that might seed beta conformations. The structures obtained might help to find regions that are more affected by environmental conditions in vivo. This could in turn aid the design of molecules able to inhibit fibril deposition or revert oligomerization processes.