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Multiscale simulations reveal TDP-43 molecular-level interactions driving condensation

Journal Article · · Biophysical Journal
 [1];  [2];  [3];  [2];  [4];  [5];  [6];  [7];  [1]
  1. Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
  2. Texas A&M College of Engineering, College Station, TX (United States)
  3. Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States); University of California, Santa Barbara, CA (United States)
  4. University of Lyon (France); Centre National de la Recherche Scientifique (CNRS) (France); École Normale Supérieure de Lyon (France); Université Claude Bernard Lyon 1 (France)
  5. University of Groningen (Netherlands)
  6. University of California, Santa Barbara, CA (United States)
  7. Texas A&M College of Engineering, College Station, TX (United States); Texas A&M University, College Station, TX (United States)
+ Show Author Affiliations
The RNA-binding protein TDP-43 is associated with mRNA processing and transport from the nucleus to the cytoplasm. TDP-43 localizes in the nucleus as well as accumulating in cytoplasmic condensates such as stress granules. Aggregation and formation of amyloid-like fibrils of cytoplasmic TDP-43 are hallmarks of numerous neurodegenerative diseases, most strikingly present in >90% of amyotrophic lateral sclerosis (ALS) patients. If excessive accumulation of cytoplasmic TDP-43 causes, or is caused by, neurodegeneration is presently not known. In this work, we use molecular dynamics simulations at multiple resolutions to explore TDP-43 self- and cross-interaction dynamics. A full-length molecular model of TDP-43, all 414 amino acids, was constructed from select structures of the protein functional domains (N-terminal domain, and two RNA recognition motifs, RRM1 and RRM2) and modeling of disordered connecting loops and the low complexity glycine-rich C-terminus domain. All-atom CHARMM36m simulations of single TDP-43 proteins served as guides to construct a coarse-grained Martini 3 model of TDP-43. The Martini model and a coarser implicit solvent Cα model, optimized for disordered proteins, were subsequently used to probe TDP-43 interactions; self-interactions from single-chain full-length TDP-43 simulations, cross-interactions from simulations with two proteins and simulations with assemblies of dozens to hundreds of proteins. Our findings illustrate the utility of different modeling scales for accessing TDP-43 molecular-level interactions and suggest that TDP-43 has numerous interaction preferences or patterns, exhibiting an overall strong, but dynamic, association and driving the formation of biomolecular condensates.
Research Organization:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Organization:
National Institutes of Health (NIH); National Science Foundation (NSF); USDOE National Nuclear Security Administration (NNSA)
Grant/Contract Number:
AC52-07NA27344
OSTI ID:
2204959
Report Number(s):
LLNL--JRNL-840812; 1061352
Journal Information:
Biophysical Journal, Journal Name: Biophysical Journal Journal Issue: 22 Vol. 122; ISSN 0006-3495
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
ALS
CHARMM36m
Coarse-grained
Martini 3
biomolecular condensates
intrinsically disordered proteins
liquid-liquid phase separation