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

Ruiting Li; Ruhar Singh; Tara Kashav; ChunMin Yang; Ravi Datta Sharma; Andrew M Lynn; Rajendra Prasad; Amresh Prakash; Vijay Kumar

doi:10.3389/fnmol.2022.822863

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

Front Mol Neurosci. 2022 Apr 25:15:822863. doi: 10.3389/fnmol.2022.822863. eCollection 2022.

Authors

Ruiting Li¹, Ruhar Singh², Tara Kashav³, ChunMin Yang¹, Ravi Datta Sharma⁴, Andrew M Lynn², Rajendra Prasad⁴, Amresh Prakash⁵, Vijay Kumar⁶

Affiliations

¹ School of Engineering, Guangzhou College of Technology and Business, Guangzhou, China.
² School of Computational & Integrative Sciences, Jawaharlal Nehru University, New Delhi, India.
³ Department of Life Science, Central University of South Bihar, Gaya, India.
⁴ Amity Institute of Biotechnology, Amity University Haryana, Gurgaon, India.
⁵ Amity Institute of Integrative Sciences and Health (AIISH), Amity University Haryana, Gurgaon, India.
⁶ Amity Institute of Neuropsychology & Neurosciences (AINN), Amity University, Noida, India.

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.

Keywords: DMSO; NTD; TDP-43; conformational heterogeneity; unfolding intermediates.