From Maxwell Fluid to Kelvin Voigt Solid: A Transient Network Model of Condensate Aging and Morphology Transition in Phase Separation

Abstract

Biomolecular condensates can undergo striking changes, such as transitioning from a liquid-like to a gel- or a solid-like aggregate due to changes in molecular interactions in response to changes in the biochemical environment. The question of how modified molecular interactions lead to such a transition in the material properties and spatial organization of condensates has not yet been elucidated. To address this question, we represent the biochemical environment as a triphasic mixture comprising a liquid-like protein-rich phase, a network-like protein-rich phase, and solvent. Owing to a change in the biochemical environment, protein molecules can reversibly switch between two conformational states. In a switched conformational state, the cross-linking domains of molecules are exposed which promote transient network formation in phase separated states. We develop a transient-network model and a continuum framework that couples phase separation, molecular switching, and dynamic cross-linking to predict condensate morphology and mechanics. The transient-network model predicts that a non-aging network behaves like a Maxwell fluid. When a network slowly ages via stabilization of cross-links, it shows Maxwell-like behavior and waiting time-dependent relaxation. However, a strongly aged network shows elastic recoil like characteristic of a Kelvin-Voigt solid. Our coupled continuum model demonstrates that the interplay of molecular switching and dynamic cross-linking in network formation shapes the spatial organization of condensate phases. In summary, this work demonstrates a mechanistic route explaining how conformational switching and molecular cross-linking regulate material properties and morphology of condensates.