Protein phase transition can generate non-membrane bound cellular compartments, which can convert from liquid-like to solid-like states. While the molecular driving forces of phase separation have been largely understood, much less is known about the mechanisms of material-state conversion. We apply a recently developed algorithm to describe the weak interaction network of multivalent motifs, and simulate the effect of pathological mutations. We demonstrate that linker dynamics is critical to the material-state of biomolecular condensates. We show that linker flexibility/mobility is a major regulator of the weak, heterogeneous meshwork of multivalent motifs, which promotes phase transition and maintains a liquid-like state. Decreasing linker dynamics increases the propensity of amyloid-like fragments via hampering the motif-exchange and reorganization of the weak interaction network. In contrast, increasing linker mobility may compensate rigidifying mutations, suggesting that the meshwork of weak, variable interactions may provide a rescue mechanism from aggregation. Motif affinity, on the other hand, has a moderate impact on fibrillization. Here we demonstrate that the fuzzy framework provides an efficient approach to handle the intricate organization of membraneless organelles, and could also be applicable to screen for pathological effects of mutations.

Spatiotemporal regulation of the biochemical information is often linked to supramolecular organizations proteins and nucleic acids, the driving forces of which have yet to be elucidated. Although the critical role of multivalency in phase transition has been recognized, the organization principles of higher-order structures need to be understood. Here, we present a fuzzy mathematical framework to handle the heterogeneity of interactions patterns and the resultant multiplicity of conformational states in protein assemblies. In this model, redundant binding motifs can establish simultaneous and partial interactions with multiple targets. We demonstrate that these multivalent, weak contacts facilitate polymer formation, while recapitulating the observed valency-dependence. In addition, the impact of linker dynamics and motif binding affinity, as well as the interplay between the two effects was studied. Our results support that fuzziness is a critical factor in driving higher-order protein organizations, and this could be used as a general framework to simulate different kinds of supramolecular assemblies.