The biomolecular condensation of proteins with low complexity sequences plays a functional role in RNA metabolism and a pathogenic role in neurodegenerative diseases. The formation of dynamic liquid droplets brings biomolecules together to achieve complex cellular functions. The rigidification of liquid droplets into β-strand-rich hydrogel structures composed of protein fibrils is thought to be purely pathological in nature. However, low complexity sequences often harbor multiple fibrilprone regions with delicately balanced functional and pathological interactions. Here, we investigate the maturation of liquid droplets formed by the low complexity domain of the TAR DNA-binding protein 43 (TDP-43). Solid state nuclear magnetic resonance measurements on the aged liquid droplets identify residues 365−400 as the structured core, which are squarely outside the region between residues 311−360 thought to be most important for pathological fibril formation and aggregation. The results of this study suggest that multiple segments of this low complexity domain are prone to form fibrils and that stabilization of β-strand-rich structure in one segment precludes the other region from adopting a rigid fibril structure.

In an ultrahigh vacuum chamber, an alkylbenzene was deposited from the vapor phase onto a cryogenically cooled Al 2 O 3 surface. An additional layer with a fluorophore of naphthalene or methylnaphthalene was deposited, and the bilayer was optically pumped. Vapor-deposited naphthalene and methyl-substituted naphthalene molecules on the surface of Al 2 O 3 are amorphously arranged and exhibit a characteristic excimeric fluorescence that is spectrally broad, featureless, and redshifted relative to the monomer fluorescence. When the bilayer was heated in a temperature-programmed desorption (TPD) experiment, the ordering in the alkylbenzene substrate caused the overlayer of naphthalenes to crystalize due to heteroepitaxy. Finally, the two layers mixed when the surface temperature was nearly at the desorption temperature and resonance energy transfer was observed from the alkylbenzene to naphthalene and methylnaphthalenes when the alkylbenzene percolated through the naphthalene and methylnaphthalene adlayers. The wavelength-resolved TPD and laser-induced fluorescence of the bilayer are reported. Reformation of the excimer after the passage of the alkylbenzene occurred for weak alkylbenzene−naphthalene interaction, whereas for strong interaction, the naphthalene monomer emission persisted after desorption of the alkylbenzene.

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Understanding the conformational ensemble of an intrinsically disordered protein (IDP) is of great interest due to its relevance to important intracellular functions and diseases. We have recently shown that the polymer scaling exponent characterizing the dependence of protein size on chain length is a crucial factor as it strongly correlates with liquid-liquid phase behavior of an IDP. Previously, sequence properties from charged amino acids, including both fraction of positive/negative charges and charge patterning have been acknowledged to affect the size of an IDP. However, IDP sequences are composed of a significant amount of uncharged amino acids and how these uncharged amino acids impact the size of an IDP is not well understood. Here, we first investigate if average hydrophobicity can be used to obtain quantitative insights into the polymer scaling properties of IDP sequences. Based on the coarse-grained simulation data for a large number of uncharged IDPs, we find that incorporating the information about the patterning of residues is necessary to model the size of an IDP faithfully. The newly developed sequence hydrophobicity decoration (SHD) parameter, together with the previously known sequence charge decoration (SCD) parameter, can be used to predict the size of an IDP. Our results are, therefore, a significant step forward to elucidate the fundamental principles governing the sequence-structure relationships of disordered proteins.

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