Department of Chemistry, University of California-Irvine, Irvine, CA 92697-2025, USA.
J Phys Chem A. 2013 Jan 17;117(2):342-50. doi: 10.1021/jp3101267. Epub 2013 Jan 7.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of plaque deposits in the human brain. The main component of these plaques consists of highly ordered structures called amyloid fibrils, formed by the amyloid β-peptide (Aβ). The mechanism connecting Aβ and AD is yet undetermined. In a previous study, a coarse-grained united-residue model and molecular dynamics simulations were used to model the growth mechanism of Aβ amyloid fibrils. On the basis of these simulations, a dock/lock mechanism was proposed, in which Aβ fibrils grow by adding monomers at either end of an amyloid fibril template. To examine the structures in the early time-scale formation and growth of amyloid fibrils, simulated two-dimensional ultraviolet spectroscopy is used. These early structures are monitored in the far ultraviolet regime (λ = 190-250 nm) in which the computed signals originate from the backbone nπ* and ππ* transitions. These signals show distinct cross-peak patterns that can be used, in combination with molecular dynamics, to monitor local dynamics and conformational changes in the secondary structure of Aβ-peptides. The protein geometry-correlated chiral xxxy signal and the non-chiral combined signal xyxy-xyyx were found to be sensitive to, and in agreement with, a dock/lock pathway.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是人类大脑中斑块沉积物的积累。这些斑块的主要成分由高度有序的结构组成，称为淀粉样纤维，由淀粉样 β 肽（Aβ）形成。将 Aβ 与 AD 联系起来的机制尚不确定。在之前的一项研究中，使用粗粒度统一残基模型和分子动力学模拟来模拟 Aβ 淀粉样纤维的生长机制。在此基础上提出了一种对接/锁定机制，其中 Aβ 纤维通过在淀粉样纤维模板的两端添加单体来生长。为了研究淀粉样纤维早期形成和生长的结构，使用模拟二维紫外光谱法。在远紫外区（λ=190-250nm）监测这些早期结构，其中计算出的信号源于骨架 nπ和 ππ跃迁。这些信号显示出明显的交叉峰模式，可与分子动力学结合使用，以监测 Aβ-肽二级结构中的局部动力学和构象变化。发现与蛋白质几何相关的手性 xxxy 信号和非手性组合信号 xyxy-xyyx 对对接/锁定途径敏感且与之一致。
