Amyloid-β (Aβ) fibrils and plaques are one of the hallmarks of Alzheimer's disease. While the kinetics of fibrillar growth of Aβ have been extensively studied, several vital questions remain. In particular, the atomistic origins of the Arrhenius barrier observed in experiments have not been elucidated. Employing the familiar thermodynamic integration method, we have directly simulated the dissociation of an Aβ(15-40) (D23N mutant) peptide from the surface of a filament along its most probable path (MPP) using all-atom molecular dynamics. This allows for a direct calculation of the free energy profile along the MPP, revealing a multipeak energetic barrier between the free peptide state and the aggregated state. By definition of the MPP, this simulated unbinding process represents the reverse of the physical elongation pathway, allowing us to draw biophysically relevant conclusions from the simulation data. Analyzing the detailed atomistic interactions along the MPP, we identify the atomistic origins of these peaks as resulting from the dock-lock mechanism of filament elongation. Careful analysis of the dynamics of filament elongation could prove key to the development of novel therapeutic strategies for amyloid-related diseases.

中文翻译：

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淀粉样β-原纤维伸长的热力学：过渡态的原子细节。

淀粉样蛋白β（Aβ）的原纤维和噬菌斑是阿尔茨海默氏病的标志之一。尽管已经广泛研究了Aβ的原纤维生长动力学，但仍然存在一些重要的问题。特别是，尚未阐明实验中观察到的阿伦尼乌斯屏障的原子起源。使用熟悉的热力学积分方法，我们已使用全原子分子动力学直接模拟了Aβ（15-40）（D23N突变体）肽从细丝表面沿其最可能路径（MPP）的解离。这允许直接计算沿MPP的自由能分布，从而揭示了游离肽态和聚集态之间的多峰能量屏障。根据MPP的定义，这种模拟的脱键过程代表了物理延伸途径的逆过程，让我们可以从模拟数据中得出与生物物理相关的结论。分析沿MPP的详细原子相互作用，我们确定了这些峰的原子起源，这是由长丝伸长的对接锁机制引起的。细丝伸长动力学的仔细分析可能被证明是开发淀粉样蛋白相关疾病新治疗策略的关键。