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Research Article
Insights into the Aggregation Mechanism of RRM domains in TDP-43: A Molecular Dynamics Study
Chaoqun Li
Hebei Key Laboratory of Heterocyclic Compounds, College of Chemistry, Chemical Engineering and Materials, Handan University, Handan, 056005, Hebei Province
Corresponding Author
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The transactive response DNA-binding protein 43 (TDP-43) is associated with several diseases such as Amyotrophic lateral sclerosis (ALS) and Frontotemporal lobar degeneration (FTLD) due to pathogenic aggregations. In this work, we examined the dimer, tetramer and hexamer models built from the RRM domains of TDP-43 using molecular dynamics simulations in combination with the protein-protein docking. Our results show that the parallel β-sheet layers in the RRM1 domains in these oligomer models were formed energetically favorable, which provide the potential binding sites in the aggregation process. The closeness of the parallel β-sheet layers from small oligomer models gradually expanded to large ones through the communication of the interaction between α1/α2 helices of RRM domains, which enhanced the binding affinities and interactions in these aggregation models to further promote the aggregation. Using the repeatable-superimposing method based on the tetramer models, we propose a new aggregation mechanism of RRM domains in TDP-43 which mediates the formation of large aggregation structure with the repeated, helical and rope-like characteristics. These new insights help to understand the amyloid-like aggregation phenomena of TDP-43 protein in ALS and FTLD diseases.
Keywords
TDP-43 protein, RRM1 and RRM2 domain, molecular dynamics simulation, aggregation
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This is a preprint. It has not completed peer review.
Research Article
Insights into the Aggregation Mechanism of RRM domains in TDP-43: A Molecular Dynamics Study
Chaoqun Li
Hebei Key Laboratory of Heterocyclic Compounds, College of Chemistry, Chemical Engineering and Materials, Handan University, Handan, 056005, Hebei Province
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 15 Dec, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
The transactive response DNA-binding protein 43 (TDP-43) is associated with several diseases such as Amyotrophic lateral sclerosis (ALS) and Frontotemporal lobar degeneration (FTLD) due to pathogenic aggregations. In this work, we examined the dimer, tetramer and hexamer models built from the RRM domains of TDP-43 using molecular dynamics simulations in combination with the protein-protein docking. Our results show that the parallel β-sheet layers in the RRM1 domains in these oligomer models were formed energetically favorable, which provide the potential binding sites in the aggregation process. The closeness of the parallel β-sheet layers from small oligomer models gradually expanded to large ones through the communication of the interaction between α1/α2 helices of RRM domains, which enhanced the binding affinities and interactions in these aggregation models to further promote the aggregation. Using the repeatable-superimposing method based on the tetramer models, we propose a new aggregation mechanism of RRM domains in TDP-43 which mediates the formation of large aggregation structure with the repeated, helical and rope-like characteristics. These new insights help to understand the amyloid-like aggregation phenomena of TDP-43 protein in ALS and FTLD diseases.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11
Figure 12
Due to technical limitations, full-text HTML conversion of this manuscript could not be completed. However, the latest manuscript can be downloaded and accessed as a PDF.