Elucidation of the structural stability and dynamics of heterogeneous intermediate ensembles in unfolding pathway of the N-terminal domain of TDP-43.

ABSTRACT: The N-terminal domain of the RNA binding protein TDP-43 (NTD) is essential to both physiology and proteinopathy; however, elucidation of its folding/unfolding still remains a major quest. In this study, we have investigated the biophysical behavior of intermediate ensembles employing all-atom molecular dynamics simulations in 8 M urea accelerated with high temperatures to achieve unfolded states in a confined computation time. The cumulative results of the 2.75 μs simulations show that unfolding of the NTD at 350 K evolves through different stable and meta-stable intermediate states. The free-energy landscape reveals two meta-stable intermediates (I_N and I_U) stabilized by non-native interactions, which are largely hydrophilic and highly energetically frustrated. A sin

SUBMITTER: Prakash A 

PROVIDER: S-EPMC9088055 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature