Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139-4301, USA.
Biochemistry. 2010 Oct 19;49(41):8967-77. doi: 10.1021/bi100953t.
The identification of more efficient therapies for defeating severe degenerative diseases like Alzheimer's is a major goal of drug discovery research. Realizing this ambitious goal will likely require a series of molecular insights that shed light on the fundamental mechanisms that drive the formation, growth, stability, and toxicity of Aβ(1-40) amyloid fibrils, one of the most abundant species found in affected brain tissues and potentially a major player in the progression of Alzheimer's disease. Amyloid fibrils feature a highly ordered and dense network of hydrogen bonds, a universal feature of all amyloid structures, which is realized by a highly regular stacking of small β-units that are each stabilized by an intrapeptide salt bridge. Here we report a series of molecular dynamics simulations of large-scale amyloid fibrils with local mutations that result in the disruption of the key intrapeptide salt bridge. We demonstrate that mutations, through alterations in the nature of the salt bridge, have a significant effect on the geometry and mechanical properties of the amyloid fibril. We specifically observe a severe decrease in amyloid fibril periodicity (the period length) of up to 43%, and extreme variations of the Young's modulus (a measure of the fibril's mechanical stiffness) of up to 154%. These results confirm that, while on one hand side chains are not involved in the formation of the β-strands composing the inner core of the amyloid structure, their presence, size, and interactions can be crucial in determining the larger-scale properties of amyloid fibrils. Our results imply that interactions mediated by side chains could be a potential target for novel approaches to drug design and the development of molecular therapies for amyloid disorders such as Alzheimer's disease, through the chemical deactivation of key functional groups that are responsible for promoting the growth of the fibrils, for promoting their chemical and mechanical stability, and for furthering their aggregation in amyloid plaques.
鉴定出更有效的疗法来攻克阿尔茨海默病等严重退行性疾病是药物发现研究的主要目标。要实现这一宏伟目标，可能需要一系列分子见解，以揭示驱动 Aβ（1-40）淀粉样纤维形成、生长、稳定性和毒性的基本机制，淀粉样纤维是受影响脑组织中最丰富的物质之一，也是阿尔茨海默病进展的主要因素之一。淀粉样纤维的特征是具有高度有序和密集的氢键网络，这是所有淀粉样结构的普遍特征，由高度规则的小β-单元堆积实现，每个单元都由肽内盐桥稳定。在这里，我们报告了一系列具有局部突变的大规模淀粉样纤维的分子动力学模拟，这些突变导致关键肽内盐桥的破坏。我们证明，突变通过改变盐桥的性质，对淀粉样纤维的几何形状和机械性能有显著影响。我们特别观察到淀粉样纤维周期性（周期长度）严重下降高达 43%，以及杨氏模量（衡量纤维机械刚度的指标）极端变化高达 154%。这些结果证实，一方面侧链不参与构成淀粉样结构内部核心的β-链的形成，但它们的存在、大小和相互作用可能对淀粉样纤维的更大规模性质至关重要。我们的研究结果表明，侧链介导的相互作用可能成为药物设计和开发针对阿尔茨海默病等淀粉样紊乱的分子疗法的新方法的潜在目标，通过化学失活负责促进纤维生长、促进其化学和机械稳定性以及促进其在淀粉样斑块中聚集的关键功能基团。
