Fig. 5: Structural model of the tetrameric helical assembly of TDP-43 CR.
A Potential multimeric structures (trimer, tetramer, hexamer, octamer) of TDP-43310-350 fragment are predicted using AF2-Multimer. The model confidence score (0.8 × ipTM + 0.2 × pTM) of predicted structures for different multimeric states is compared with that of AF2-Multimer predicted tetrameric structures of homotetrameric coiled-coil sequence (CC-tet, 4-KE-470), which served as a control. B AF2-Multimer predicted multimeric structures are then fed to run all-atom MD (AAMD) simulations (~4–5 μs each) and structural stability was assessed by computing the distance root-mean-square (dRMS) of heavy atoms (residues 320–341, excluding hydrogens) relative to the initial conformations. The time evolution of dRMS values is shown. The dRMS values of the trimers are represented in dark green, tetramers in orange (with Tet-1 and Tet-2 specifically highlighted in red and blue, respectively), hexamers in magenta, and octamers in cyan. (See Supplementary Fig. 11A for more details). C dRMS distributions from AAMD simulations (50 independent replicates with 100 ns each) of selected tetramer models (Tet-1 and Tet-2) are shown. The lighter colors represent the dRMS distributions for independent runs, while the darker colors represent the average dRMS distributions from 50 replicates. Tet-1 exhibits greater stability compared to Tet-2. D (top) Pairwise intermolecular contact maps of Tet-1 from AAMD simulations (single run, 5 μs). (bottom) Total number of contacts per residue position (Ncontact) derived through summation of all pairwise contacts along y-axis based on two dimensional pairwise intermolecular contact map. Reported as mean ± SEM using block averaging over 5 time blocks. E Representative structure of the CR (aa: 319–341) of Tet-1 from the last microsecond of AAMD simulations (single run, 5 μs) are shown. Parallel helices are shown as yellow (chain 1 & 3) and light green (chain 2 & 4) colored ribbons. Side chains (excluding hydrogen atoms) of CR residues that are in the core (left) and in contact between adjacent helices (right) are shown as sticks, with their colors indicating different residue types as illustrated in the right corner. Source data are provided as a Source Data file.
