Fig. 3. Inter-molecular interactions within protein condensates in health and disease.

A Interaction modes of residues in the prion-like domain of TDP-43 vary between disordered and ordered modes. The interaction motifs that promote the formation of the condensed states of this protein are influenced by their flanking regions. The TDP-43 amyloid-core region (residues 321–330, orange) and the flanking aggregation hot-spots (residues 312–320 and 331–342, yellow) sample both ordered and disordered interactions (multi-modal binding). In contrast, most residues outside these regions are droplet-promoting (residues 262–311 and 343–414, blue), which sample mostly disordered interactions (unimodal binding). B The droplet landscape of TDP-43 prion-like domain illustrates the conversion between droplet and amyloid states. The likelihood of aggregation within droplets depends on two features⁹⁹, the residue-specific multiplicity of binding modes (MBM) and the probability of undergoing liquid–liquid phase separation (LLPS). The multiplicity of binding modes characterises the ability of sampling both disordered interactions, which bias towards the droplet state (blue, based on PDB: 2N3X¹⁴⁸), and ordered interactions, which bias towards the amyloid state (PDB:7KWZ¹⁴⁹, orange). Both properties can be predicted from the sequence using the FuzDrop method (https://fuzdrop.bio.unipd.it)⁸. Droplet-promoting regions (blue circles) have a low multiplicity of binding modes in contrast to the amyloid core (orange triangles) and aggregation hot-spots (yellow diamonds), which exhibit high multiplicity of binding modes (large y values)⁹⁹. C The sequence of the amyloidogenic region of TDP-43 (residues 311–360) is shown corresponding to the solution structure (PDB: 2N3X). The amyloid core is shown by orange, the aggregation hot-spot by yellow and the flanking residues by blue. The liquid–liquid phase separation of the prion-like domain of TDP-43 depends on the presence of an α-helical structural element¹²⁵.