Jeong‐Mo Choi

Many biomolecular condensates appear to form via spontaneous or driven processes that have the hallmarks of intracellular phase transitions. This suggests that a common underlying physical framework might govern the formation of functionally and compositionally unrelated biomolecular condensates. In this review, we summarize recent work that leverages a stickers-and-spacers framework adapted from the field of associative polymers for understanding how multivalent protein and RNA molecules drive phase transitions that give rise to biomolecular condensates. We discuss how the valence of stickers impacts the driving forces for condensate formation and elaborate on how stickers can be distinguished from spacers in different contexts. We touch on the impact of sticker- and spacer-mediated interactions on the rheological properties of condensates and show how the model can be mapped to known drivers of different types of biomolecular condensates.

Many biomolecular condensates form via spontaneous phase transitions that are driven by multivalent proteins. These molecules are biological instantiations of associative polymers that conform to a so-called stickers-and-spacers architecture. The stickers are protein-protein or protein-RNA interaction motifs and / or domains that can form reversible, non-covalent crosslinks with one another. Spacers are interspersed between stickers and their preferential interactions with solvent molecules determine the cooperativity of phase transitions. Here, we report the development of an open source computational engine known as LASSI (LAttice simulation engine for Sticker and Spacer Interactions) that enables the calculation of full phase diagrams for multicomponent systems comprising of coarse-grained representations of multivalent proteins. LASSI is designed to enable computationally efficient phenomenological modeling of spontaneous phase transitions of multicomponent mixtures comprising of multivalent proteins and RNA molecules. We demonstrate the application of LASSI using simulations of linear and branched multivalent proteins. We show that dense phases are best described as droplet-spanning networks that are characterized by reversible physical crosslinks among multivalent proteins. We connect recent observations regarding correlations between apparent stoichiometry and dwell times of condensates to being proxies for the internal structural organization, specifically the convolution of internal density and extent of networking, within condensates. Finally, we demonstrate that the concept of saturation concentration thresholds does not apply to multicomponent systems where obligate heterotypic interactions drive phase transitions. This emerges from the ellipsoidal structures of phase diagrams for multicomponent systems and it has direct implications for the regulation of biomolecular condensates in vivo.

Statistical mechanics underlies our understanding of macroscopic quantum systems. It is based on the assumption that out-of-equilibrium systems rapidly approach their equilibrium states, forgetting any information about their microscopic initial conditions. This fundamental paradigm is challenged by disordered systems, in which a slowdown or even absence of thermalization is expected. We report the observation of critical thermalization in a three dimensional ensemble of ∼10^{6} electronic spins coupled via dipolar interactions. By controlling the spin states of nitrogen vacancy color centers in diamond, we observe slow, subexponential relaxation dynamics and identify a regime of power-law decay with disorder-dependent exponents; this behavior is modified at late times owing to many-body interactions. These observations are quantitatively explained by a resonance counting theory that incorporates the effects of both disorder and interactions.

Polymers with stickers-and-spacers architectures can drive phase-separation-aided bond percolation transitions. Here, we present a generalized mean-field model to enable the calculation of bond percolation thresholds for polymers with multiple types of stickers. Further, using graph-based Monte Carlo simulations we demonstrate how cooperativity in bond formation can give rise to reentrant phase behavior. When combined with recent advances for modeling phase separation, our approaches for calculating percolation lines could be useful for modeling hardening transitions for multivalent proteins.