Computational Investigation of RNA A-Bulges Related to the Microtubule-Associated Protein Tau Causing Frontotemporal Dementia and Parkinsonism
| Autor: | Matthew D. Disney, Ilyas Yildirim, David J. Wales |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Tau protein
tau Proteins Computational biology Molecular Dynamics Simulation 010402 general chemistry 01 natural sciences Article Parkinsonian Disorders Microtubule associated protein tau 0103 physical sciences Materials Chemistry medicine Humans Physical and Theoretical Chemistry Gene Quantitative Biology::Biomolecules Messenger RNA 010304 chemical physics biology Chemistry Parkinsonism Alternative splicing RNA medicine.disease Quantitative Biology::Genomics 0104 chemical sciences Surfaces Coatings and Films Frontotemporal Dementia biology.protein Frontotemporal dementia |
| Zdroj: | The Journal of Physical Chemistry B. 123:57-65 |
| ISSN: | 1520-5207 1520-6106 |
| Popis: | Mutations in the human tau gene result in alternative splicing of the tau protein, which causes frontotemporal dementia and Parkinsonism. One disease mechanism is linked to the stability of a hairpin within the microtubule-associated protein tau (MAPT) mRNA, which contains an A-bulge. Here we employ computational methods to investigate the structural and thermodynamic properties of several A-bulge RNAs with different closing base-pairs. We find that the current amber RNA force field has a preference to overstabilize base-triple over stacked states, even though some of the A-bulges are known to prefer stacked states according to NMR studies. We further determined that if the neighboring base-pairs of A-bulges are AU, this situation can lead to base slippage. However, when the 3′-side of the A-bulge has an UA base-pair, the stacked state is stabilized by an extra interaction that is not observed in the other sequences. We suggest that these A-bulge RNA systems could be used as benchmarks to improve the current RNA force fields. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|