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Fibril Surface-Dependent Amyloid Precursors Revealed by Coarse-Grained Molecular Dynamics Simulation

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 pro...

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Autores principales: Ma, Yuan-Wei, Lin, Tong-You, Tsai, Min-Yeh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378332/
https://www.ncbi.nlm.nih.gov/pubmed/34422910
http://dx.doi.org/10.3389/fmolb.2021.719320
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author Ma, Yuan-Wei
Lin, Tong-You
Tsai, Min-Yeh
author_facet Ma, Yuan-Wei
Lin, Tong-You
Tsai, Min-Yeh
author_sort Ma, Yuan-Wei
collection PubMed
description 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.
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spelling pubmed-83783322021-08-21 Fibril Surface-Dependent Amyloid Precursors Revealed by Coarse-Grained Molecular Dynamics Simulation Ma, Yuan-Wei Lin, Tong-You Tsai, Min-Yeh Front Mol Biosci Molecular Biosciences 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. Frontiers Media S.A. 2021-08-06 /pmc/articles/PMC8378332/ /pubmed/34422910 http://dx.doi.org/10.3389/fmolb.2021.719320 Text en Copyright © 2021 Ma, Lin and Tsai. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Ma, Yuan-Wei
Lin, Tong-You
Tsai, Min-Yeh
Fibril Surface-Dependent Amyloid Precursors Revealed by Coarse-Grained Molecular Dynamics Simulation
title Fibril Surface-Dependent Amyloid Precursors Revealed by Coarse-Grained Molecular Dynamics Simulation
title_full Fibril Surface-Dependent Amyloid Precursors Revealed by Coarse-Grained Molecular Dynamics Simulation
title_fullStr Fibril Surface-Dependent Amyloid Precursors Revealed by Coarse-Grained Molecular Dynamics Simulation
title_full_unstemmed Fibril Surface-Dependent Amyloid Precursors Revealed by Coarse-Grained Molecular Dynamics Simulation
title_short Fibril Surface-Dependent Amyloid Precursors Revealed by Coarse-Grained Molecular Dynamics Simulation
title_sort fibril surface-dependent amyloid precursors revealed by coarse-grained molecular dynamics simulation
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378332/
https://www.ncbi.nlm.nih.gov/pubmed/34422910
http://dx.doi.org/10.3389/fmolb.2021.719320
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