Phase separation of, in particular, intrinsically disordered proteins into condensates is a ubiquitous process by which cells regulate a plethora of biological processes. In aberrant cases, such as encountered in neurodegeneration, these initially liquid condensates “age” to become more solid like. Understanding the interplay between phase separation and aging seems essential in the development of new therapeutic strategies. Our approach to generating such insight is by applying minimal models that aim to capture the essence of biological transitions in terms of driving forces and thermodynamics. Minimal models capable of discriminating between mono- and multivalent directed association on the one hand and non-specific, non-saturating interactions on the other appear to be surprisingly versatile in reproducing and predicting biopolymer phase behavior, while at the same time providing essential mechanistic insight. We will give an overview of our work in this field, combining theory with experiments and demonstrating how relatively simple descriptions can (re)produce complex multi-component phase behavior. We will also present a dynamic version of the model, which provides for a thermodynamically fully consistent and intuitive description of the experimentally observed changes in viscoelasticity during aging of IDP condensates. Our calculations explain, for instance, how the “stickiness” of the proteins changes with time and concentration, how the coupling between association and solvation determines viscoelasticity, and how aging proceeds in a spatially anisotropic way across the condensate.
Michels et al. (Sun,) studied this question.