DataSheet1_Fibril Surface-Dependent Amyloid Precursors Revealed by Coarse-Grained Molecular Dynamics Simulation.pdf

Amyloid peptides are known to self-assemble into larger aggregates that are linked to the pathogenesis of many neurodegenerative disorders. In contrast to primary nucleation, recent experimental and theoretical studies have shown that many toxic oligomeric species are generated through secondary processes on a pre-existing fibrillar surface. Nucleation, for example, can also occur along the surface of a pre-existing fibril—secondary nucleation—as opposed to the primary one. However, explicit pathways are still not clear. In this study, we use molecular dynamics simulation to explore the free energy landscape of a free Abeta monomer binding to an existing fibrillar surface. We specifically look into several potential Abeta structural precursors that might precede some secondary events, including elongation and secondary nucleation. We find that the overall process of surface-dependent events can be described at least by the following three stages: 1. Free diffusion 2. Downhill guiding 3. Dock and lock. And we show that the outcome of adding a new monomer onto a pre-existing fibril is pathway-dependent, which leads to different secondary processes. To understand structural details, we have identified several monomeric amyloid precursors over the fibrillar surfaces and characterize their heterogeneity using a probability contact map analysis. Using the frustration analysis (a bioinformatics tool), we show that surface heterogeneity correlates with the energy frustration of specific local residues that form binding sites on the fibrillar structure. We further investigate the helical twisting of protofilaments of different sizes and observe a length dependence on the filament twisting. This work presents a comprehensive survey over the properties of fibril growth using a combination of several openMM-based platforms, including the GPU-enabled openAWSEM package for coarse-grained modeling, MDTraj for trajectory analysis, and pyEMMA for free energy calculation. This combined approach makes long-timescale simulation for aggregation systems as well as all-in-one analysis feasible. We show that this protocol allows us to explore fibril stability, surface binding affinity/heterogeneity, as well as fibrillar twisting. All these properties are important for understanding the molecular mechanism of surface-catalyzed secondary processes of fibril growth.

淀粉样肽（Amyloid peptides）可自组装形成更大的聚集体，此类聚集体与诸多神经退行性疾病的发病机制紧密相关。相较于初级成核，近期的实验与理论研究表明，诸多毒性寡聚体物种是通过预先存在的原纤维表面上的次级过程生成的。例如，与之相对，成核过程亦可在预先存在的原纤维表面发生，此即为次级成核。然而，其具体的作用通路仍未明确。
本研究采用分子动力学（Molecular Dynamics, MD）模拟方法，探究游离Aβ单体与现有原纤维表面结合的自由能景观。我们重点考察了若干可能参与延伸与次级成核等次级过程的潜在Aβ结构前体。研究发现，依赖于表面的整体过程至少可分为以下三个阶段：1. 自由扩散；2. 下坡引导（Downhill guiding）；3. 锚定与锁定（Dock and lock）。同时本研究发现，向预先存在的原纤维添加新单体的结果依赖于其所遵循的通路，进而引发不同的次级过程。
为解析结构细节，我们在原纤维表面鉴定出若干单体淀粉样前体，并通过概率接触图分析对其异质性进行了表征。借助能量受挫分析（frustration analysis，一种生物信息学工具），我们发现表面异质性与原纤维结构中构成结合位点的特定局部残基的能量受挫程度相关。我们进一步研究了不同尺寸的原丝（protofilament）的螺旋扭曲现象，并观察到丝状体扭曲具有长度依赖性。
本研究结合多款基于openMM的计算平台，对原纤维生长的相关特性展开全面调研，这些平台涵盖支持图形处理器（GPU）加速、用于粗粒度建模的openAWSEM工具包，用于轨迹分析的MDTraj，以及用于自由能计算的pyEMMA。这种整合方案使得聚集体系的长时标模拟与一体化分析成为可能。我们证实，该研究方案可用于探究原纤维稳定性、表面结合亲和力/异质性以及原纤维扭曲特性。上述所有特性对于理解原纤维生长的表面催化次级过程的分子机制具有重要意义。