Computational Insights of Unfolding of N-Terminal Domain of TDP-43 Reveal the Conformational Heterogeneity in the Unfolding Pathway.

ABSTRACT: TDP-43 proteinopathies is a disease hallmark that characterizes amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The N-terminal domain of TDP-43 (NTD) is important to both TDP-43 physiology and TDP-43 proteinopathy. However, its folding and dimerization process is still poorly characterized. In the present study, we have investigated the folding/unfolding of NTD employing all-atom molecular dynamics (MD) simulations in 8 M dimethylsulfoxide (DMSO) at high temperatures. The MD results showed that the unfolding of the NTD at high temperature evolves through the formation of a number of conformational states differing in their stability and free energy. The presence of structurally heterogeneous population of intermediate ensembles was further characterized by

SUBMITTER: Li R 

PROVIDER: S-EPMC9083116 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature