Abstract
Formation of biomolecular condensates via liquid-liquid phase separation (LLPS) contributes to the organization and function of living cells, but the general physicochemical principles involved are not fully understood. The present study provides a quantitative, multiscale framework that connects single- and multi-copy, microsecond molecular dynamics simulations with the experimentally observed, micrometer-scale LLPS behavior of an 80-aa N-terminal fragment of yeast Lge1 (Lge11-80), a regulator of histone H2B ubiquitination. Analysis of protein self-interactions modeled at all-atom resolution elucidates the impact of key residues on interaction valency and establishes a link between configurational entropy, valency and compactness of proteins inside a model condensate. An analytical formalism derived from first principles describes condensate structure across different length scales as a function of the interaction valency and compactness of its molecular components. In analogy to fractal cluster formation seen in biological and non-biological colloids, the formalism provides an atomistically resolved model of a micrometer-size condensate starting from the simulated ensemble of individual protein conformers. Finally, the simulation-derived fractal dimensions of the condensates of Lge11-80 and its mutants are shown to be consistent with their in vitro LLPS behavior. The presented framework provides a general, experimentally testable description of the multiscale features of biomolecular condensates and embeds their study in a wider context of self-organization in colloidal systems.
Competing Interest Statement
The authors have declared no competing interest.
