Molecular Determinants of Selectivity in Disordered Complexes May Shed Light on Specificity in Protein Condensates

Abstract

Biomolecular condensates challenge the classical concepts of molecular recognition. The variable composition and heterogeneous conformations of liquid-like protein droplets are bottlenecks for high-resolution structural studies. To obtain atomistic insights into the organization of these assemblies, here we have characterized the conformational ensembles of specific disordered complexes, including those of droplet-driving proteins. First, we found that these specific complexes exhibit a high degree of conformational heterogeneity. Second, we found that residues forming contacts at the interface also sample many conformations. Third, we found that different patterns of contacting residues form the specific interface. In addition, we observed a wide range of sequence motifs mediating disordered interactions, including charged, hydrophobic and polar contacts. These results demonstrate that selective recognition can be realized by variable patterns of weakly defined interaction motifs in many different binding configurations. We propose that these principles also play roles in determining the selectivity of biomolecular condensates.

Protein interactions: anything new?

“…Identifying non-native interactions, based on energetic considerations, is more straightforward than identifying universal-binding motifs applicable to most proteins. Analysis of heterogeneous conformational ensembles can be helpful in this endeavor [15,65].…”

RING 3.0: fast generation of probabilistic residue interaction networks from structural ensembles

“…If we observe the contact frequency of the interface residues, there are virtually no residues with inter-chain contact frequency between 50% and 100% (Figure 2 ). This is characteristic of the fuzzy interactions which are conformational heterogeneous and show ambiguous contact patterns ( 35 '). Restricting visualization in RING of inter-chain contacts to a frequency between 0% and 50%, we can see the conformational heterogeneity of these fuzzy interactions (Figure 2 ).…”