Computational Investigation of RNA A-Bulges Related to the Microtubule-Associated Protein Tau Causing Frontotemporal Dementia and Parkinsonism.

Abstract

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.