Conformational ensembles of the TDP-43 NTD-RRM1-RRM2 domains interacting with GU-rich RNA determined by MD simulations and SAXS data
5 affiliations
- 1Université Paris-Saclay
- 2CNRS, BioCIS
- 3CNRS
- 4INSERM U1204
- 5Univ Evry Paris-Saclay, SABNP
Abstract
TAR DNA-binding protein 43 (TDP-43) is a crucial regulator of RNA metabolism whose pathological aggregation is a hallmark of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s disease. Binding to GU-rich RNA sequences via its RNA recognition motifs (RRM1 and RRM2) is known to antagonize aggregation, yet the molecular mechanisms by which RNA modulates TDP-43 conformational and supramolecular organization remain poorly understood. This limitation arises from the challenges related to the structural resolution of the inter-domain dynamics by experimental methods due to the protein intrinsically disordered regions, notably the linker connecting the N-terminal domain (NTD) to RRM1. To address this gap, we performed a combined all-atom (AA) and coarse-grained (CG) molecular dynamics (MD) investigation of a TDP-43 NTD–RRM1–RRM2 monomer in both the absence and presence of GU-rich RNA. AA simulations were carried out using the protein AMBER03ws and RNA AMBERχOL3 force fields to accurately capture protein–RNA 1 interactions. In parallel, we developed a MARTINI 3–compatible CG model for GU–rich RNA and performed CG simulations to access longer timescale conformational dynamics and extend structural trends observed with atomic accuracy. Small-angle X–ray scattering (SAXS) data were integrated to refine the conformational ensembles generated by both AA and CG simulations using the genetic algorithm judging optimization of ensembles (GAJOE). Across resolutions, our results consistently show that RNA binding reshapes the conformational ensemble of TDP-43. RNA association promotes closer packing of the RRM domains while subtly modulating the spatial arrangement of the NTD. Importantly, the ensemble refinements improve the agreement with experimental SAXS data without altering the underlying residue-level protein–protein and protein–RNA interaction network, suggesting that the conformational dynamics of the NTD-RRM1 intrinsically disordered linker is not affected by the RNA binding. As a first step toward the modeling of TDP-43–RNA oligomeric assemblies, this work establishes a validated multi-scale framework for studying the impact of RNA binding on TDP-43 self-assembly and supramolecular organization. By bridging AA atomic details, CG conformational sampling, and integration of experimental data for ensemble refinement, our approach provides accurate insight into how RNA binding regulates domain organization and conformational heterogeneity of TDP-43, shedding light onto its role in proteinopathies.
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BibTeX
@misc{feng2026conformational,
title = {{Conformational ensembles of the TDP-43 NTD-RRM1-RRM2 domains interacting with GU-rich RNA determined by MD simulations and SAXS data}},
author = {Zichen Feng and Cagla Okyay and Aurélien Thureau and David Pastré and Ahmed Bouhss and Liuba Mazzanti and Tâp Ha-Duong},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15009140/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009140/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Conformational ensembles of the TDP-43 NTD-RRM1-RRM2 domains interacting with GU-rich RNA determined by MD simulations and SAXS data
AU - Zichen Feng
AU - Cagla Okyay
AU - Aurélien Thureau
AU - David Pastré
AU - Ahmed Bouhss
AU - Liuba Mazzanti
AU - Tâp Ha-Duong
PY - 2026
DA - 2026/09/21
PB - ChemRxiv
DO - 10.26434/chemrxiv.15009140/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009140/v1
AB - TAR DNA-binding protein 43 (TDP-43) is a crucial regulator of RNA metabolism whose pathological aggregation is a hallmark of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s disease. Binding to GU-rich RNA sequences via its RNA recognition motifs (RRM1 and RRM2) is known to antagonize aggregation, yet the molecular mechanisms by which RNA modulates TDP-43 conformational and supramolecular organization remain poorly understood. This limitation arises from the challenges related to the structural resolution of the inter-domain dynamics by experimental methods due to the protein intrinsically disordered regions, notably the linker connecting the N-terminal domain (NTD) to RRM1. To address this gap, we performed a combined all-atom (AA) and coarse-grained (CG) molecular dynamics (MD) investigation of a TDP-43 NTD–RRM1–RRM2 monomer in both the absence and presence of GU-rich RNA. AA simulations were carried out using the protein AMBER03ws and RNA AMBERχOL3 force fields to accurately capture protein–RNA 1 interactions. In parallel, we developed a MARTINI 3–compatible CG model for GU–rich RNA and performed CG simulations to access longer timescale conformational dynamics and extend structural trends observed with atomic accuracy. Small-angle X–ray scattering (SAXS) data were integrated to refine the conformational ensembles generated by both AA and CG simulations using the genetic algorithm judging optimization of ensembles (GAJOE). Across resolutions, our results consistently show that RNA binding reshapes the conformational ensemble of TDP-43. RNA association promotes closer packing of the RRM domains while subtly modulating the spatial arrangement of the NTD. Importantly, the ensemble refinements improve the agreement with experimental SAXS data without altering the underlying residue-level protein–protein and protein–RNA interaction network, suggesting that the conformational dynamics of the NTD-RRM1 intrinsically disordered linker is not affected by the RNA binding. As a first step toward the modeling of TDP-43–RNA oligomeric assemblies, this work establishes a validated multi-scale framework for studying the impact of RNA binding on TDP-43 self-assembly and supramolecular organization. By bridging AA atomic details, CG conformational sampling, and integration of experimental data for ensemble refinement, our approach provides accurate insight into how RNA binding regulates domain organization and conformational heterogeneity of TDP-43, shedding light onto its role in proteinopathies.
ER -