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Elucidating Important Sites and the Mechanism for Amyloid Fibril Formation by Coarse-Grained Molecular Dynamics.

ABSTRACT: Fibrils formed by the ?-amyloid (A?) peptide play a central role in the development of Alzheimer's disease. In this study, the principles governing their growth and stability are investigated by analyzing canonical and replica-exchange molecular dynamics trajectories of A?(9-40) fibrils. In particular, an unstructured monomer was allowed to interact freely with an A? fibril template. Trajectories were generated with the coarse-grained united-residue force field, and one- and two-dimensional free-energy landscapes (FELs) along the backbone virtual-bond angle ? and backbone virtual-bond-dihedral angle ? of each residue and principal components, respectively, were analyzed. Also, thermal unbinding (unfolding) of an A? peptide from the fibril template was investigated. These analyses enable us to illustrate the entire process of A? fibril elongation and to elucidate the key residues involved in it. Several different pathways were identified during the search for the fibril conformation by the monomer, which finally follows a dock-lock mechanism with two distinct locking stages. However, it was found that the correct binding, with native hydrogen bonds, of the free monomer to the fibril template at both stages is crucial for fibril elongation. In other words, if the monomer is incorrectly bound (with nonnative hydrogen bonds) to the fibril template during the first "docking" stage, it can remain attached to it for a long time before it dissociates and either attempts a different binding or allows another monomer to bind. This finding is consistent with an experimentally observed "stop-and-go" mechanism of fibril growth.

SUBMITTER: Rojas A

PROVIDER: S-EPMC5245180 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Elucidating Important Sites and the Mechanism for Amyloid Fibril Formation by Coarse-Grained Molecular Dynamics.

Rojas Ana A Maisuradze Nika N Kachlishvili Khatuna K Scheraga Harold A HA Maisuradze Gia G GG

ACS chemical neuroscience 20161118 1

Fibrils formed by the β-amyloid (Aβ) peptide play a central role in the development of Alzheimer's disease. In this study, the principles governing their growth and stability are investigated by analyzing canonical and replica-exchange molecular dynamics trajectories of Aβ<sub>(9-40)</sub> fibrils. In particular, an unstructured monomer was allowed to interact freely with an Aβ fibril template. Trajectories were generated with the coarse-grained united-residue force field, and one- and two-dimen ...[more]

PMID: 28095675

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Project 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.

Dataset Information

Elucidating Important Sites and the Mechanism for Amyloid Fibril Formation by Coarse-Grained Molecular Dynamics.

Publications

Elucidating Important Sites and the Mechanism for Amyloid Fibril Formation by Coarse-Grained Molecular Dynamics.

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