Department of Chemistry and Biochemistry, and Department of Physics, University of California, Santa Barbara, California.
Department of Chemistry and Biochemistry, and Department of Physics, University of California, Santa Barbara, California.
Biophys J. 2012 Aug 8;103(3):576-586. doi: 10.1016/j.bpj.2012.06.027.
The amyloid-β(25-35) peptide plays a key role in the etiology of Alzheimer's disease due to its extreme toxicity even in the absence of aging. Because of its high tendency to aggregate and its low solubility in water, the structure of this peptide is still unknown. In this work, we sought to understand the early stages of aggregation of the amyloid-β(25-35) peptide by conducting simulations of oligomers ranging from monomers to tetramers. Our simulations show that although the monomer preferentially adopts a β-hairpin conformation, larger aggregates have extended structures, and a clear transition from compact β-hairpin conformations to extended β-strand structures occurs between dimers and trimers. Even though β-hairpins are not present in the final architecture of the fibril, our simulations indicate that they play a critical role in fibril growth. Our simulations also show that β-sheet structures are stabilized when a β-hairpin is present at the edge of the sheet. The binding of the hairpin to the sheet leads to a subsequent destabilization of the hairpin, with part of the hairpin backbone dangling in solution. This free section of the peptide can then recruit an extra monomer from solution, leading to further sheet extension. Our simulations indicate that the peptide must possess sufficient conformational flexibility to switch between a hairpin and an extended conformation in order for β-sheet extension to occur, and offer a rationalization for the experimental observation that overstabilizing a hairpin conformation in the monomeric state (for example, through chemical cross-linking) significantly hampers the fibrillization process.
β-淀粉样蛋白（25-35）肽在阿尔茨海默病的发病机制中起着关键作用，因为即使没有衰老，它也具有极强的毒性。由于其高度聚集倾向和在水中的低溶解度，该肽的结构仍然未知。在这项工作中，我们通过模拟从单体到四聚体的低聚物，试图了解β-淀粉样蛋白（25-35）肽聚集的早期阶段。我们的模拟表明，尽管单体优先采用β-发夹构象，但较大的聚集体具有延伸结构，并且在二聚体和三聚体之间，从紧凑的β-发夹构象到延伸的β-链结构发生明显转变。尽管β-发夹在原纤维的最终结构中不存在，但我们的模拟表明它们在原纤维生长中起着关键作用。我们的模拟还表明，当β-发夹存在于片层的边缘时，β-片层结构会得到稳定。发夹与片层的结合导致发夹随后失稳，部分发夹骨架在溶液中悬垂。然后，肽的这个自由部分可以从溶液中招募一个额外的单体，导致进一步的片层延伸。我们的模拟表明，肽必须具有足够的构象灵活性，以便在发夹和延伸构象之间切换，才能发生β-片层延伸，并且为实验观察提供了合理化解释，即在单体状态下过度稳定发夹构象（例如，通过化学交联）会显著阻碍纤维化过程。
