Fuzziness in Protein Interactions-A Historical Perspective.

The proposal that coupled folding to binding is not an obligatory mechanism for intrinsically disordered (ID) proteins was put forward 10 years ago. The notion of fuzziness implies that conformational heterogeneity can be maintained upon interactions of ID proteins, which has a functional impact either on regulated assembly or activity of the corresponding complexes. Here I review how the concept has evolved in the past decade, via increasing experimental data providing insights into the mechanisms, pathways and regulatory modes. The effects of structural diversity and transient contacts on protein assemblies have been collected and systematically analyzed (Fuzzy Complexes Database, https://protdyn-database.org). Fuzziness has also been exploited as a framework to decipher molecular organization of higher-order protein structures. Quantification of conformational heterogeneity opens exciting future perspectives for drug discovery from small molecule-ID protein interactions to supramolecular assemblies.