Numerous neurodegenerative diseases, including amyotrophic lateral sclerosis, are associated with excessive aggregation of the RNA-binding protein TDP-43 (TAR DNA-binding protein 43 kDa) in neurons. TDP-43 proteins have a strong propensity to self-associate and can form dynamic assemblies. The cover image of the November 21 issue of Biophysical Journal shows a snapshot from a coarse-grained molecular dynamics simulation in which 24 full-length TDP-43 proteins come together and form a protein assembly. The proteins assemble in a fluid-like manner, with water and ions diffusing in and out of the assembly, and individual proteins exchanging positions.

To visualize the proteins, the water and ions are peeled back, with the protein backbone shown in cyan, the N-terminal domain in blue, two RNA recognition motifs (RRM1 and RRM2) in orange and yellow, and the C-terminal helix in purple.

Determining the molecular properties of full-length TDP-43 is challenging because the protein aggregates in solution, and a large part of the 414–amino acid protein is intrinsically disordered, making it hard to sample by using simulations. Our study developed and used molecular models at multiple scales (all-atom, coarse-grained, and implicit water coarse-grained) to explore TDP-43 molecular level interactions with itself and other TDP-43 molecules. Our findings illustrate the utility of different modeling scales for assessing TDP-43 molecular-level interactions (parameters can be accessed at https://bbs.llnl.gov/tdp-43_condensation_data.html) 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.

 — Helgi I. Ingólfsson, Azamat Rizuan, Xikun Liu, Priyesh Mohanty, Paulo C. T. Souza, Siewert J. Marrink, Michael T. Bowers, Jeetain Mittal, and Joel Berry