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 the different extents of solvent exposure of Trp80 during unfolding. We suggest that these non-natives unfolded intermediate ensembles may facilitate NTD oligomerization and subsequently TDP-43 oligomerization, which might lead to the formation of irreversible pathological aggregates, characteristics of disease pathogenesis.

Importin α/β and the tug of war to keep TDP‐43 in solution: quo vadis?

“…The interplay between TDP‐43 dimerization and aggregation was investigated using equilibrium molecular dynamics (MD) simulations. [ 25 ] The NTD can sample several conformations en route to the fully folded state, and it has been hypothesized that these partially folded forms of the domain mediate aggregation rather than proper dimerization. Interestingly, the earliest structure of the NTD featured the monomeric form after exposure to denaturing conditions.…”

Expression analysis and mapping of Viral—Host Protein interactions of Poxviridae suggests a lead candidate molecule targeting Mpox

“…In both the complexes, the Rg value is 1.5 nm, suggesting that the protein structure occupies a region of space. A relatively constant Rg value suggests that the structure remains stable and relatively compact structure [82]. Hydrogen bonding is essential for maintaining the structural stability of proteins in MDS.…”

ALS-Linked A315T and A315E Mutations Enhance β-Barrel Formation of the TDP-43307–319 Hexamer: A REST2 Simulation Study

“…Molecular dynamics (MD) simulations have hitherto been widely utilized in the study of peptide folding and aggregation. − The investigations of the aggregation process and structural characteristics of TDP-43 fragments using MD simulations have emerged in recent years. − For example, Imtaiyaz Hassan and co-workers unraveled the fact that the 247 DLIIKGIS 254 fragment in the RRM2 domain of TDP-43 has the ability to self-aggregate and transit into β-sheet-rich structures by utilizing all-atom MD simulations . Lynn et al demonstrated that RRM1/RRM2 exhibit different structural stabilities by performing MD simulations at two different temperatures .…”