Fibril Surface-Dependent Amyloid Precursors Revealed by Coarse-Grained Molecular Dynamics Simulation
學年 110
學期 1
出版(發表)日期 2021-08-06
作品名稱 Fibril Surface-Dependent Amyloid Precursors Revealed by Coarse-Grained Molecular Dynamics Simulation
著者 Yuan-Wei Ma; Tong-You Lin; Min-Yeh Tsai
著錄名稱、卷期、頁數 Frontiers in Molecular Biosciences 8, 719320
摘要 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.
關鍵字 abeta, MD simulation, coarse-grained model, fibril surface, secondary nucleation, fibrillar twisting, binding sites, elongation (growth)
語言 en
ISSN 2296-889X
期刊性質 國外
收錄於 SCI Scopus
國別 CHE
出版型式 ,電子版

機構典藏連結 ( )