The stoichiometric interaction model for mesoscopic molecular dynamics simulations of liquid-liquid phase separation

Liquid-liquid phase separation (LLPS) has received considerable attention in recent years for explaining the formation of cellular biomolecular condensates. The fluidity and the complexity of their components make molecular simulation approaches indispensable for gaining structural insights. Domain-resolution mesoscopic model simulations have been explored for case in which condensates are formed by multivalent proteins with tandem domains. One problem with this approach is that interdomain pairwise interactions cannot regulate the valency of the binding domains. To overcome this problem, we propose a new potential, the stoichiometric interaction (SI) potential. First, we verified that the SI potential maintained the valency of the interacting domains for the test systems. We then examined a well-studied LLPS model system containing tandem repeats of SH3 domains and proline-rich motifs. We found that the SI potential alone cannot reproduce the phase diagram of LLPS quantitatively. We had to combine the SI and a pairwise interaction; the former and the latter represent the specific and non-specific interactions, respectively. Biomolecular condensates with the mixed SI and pairwise interaction exhibited fluidity, whereas those with the pairwise interaction alone showed no detectable diffusion. We also compared the phase diagrams of the systems containing different numbers of tandem domains with those obtained from the experiments, and found quantitative agreement in all but one case. SIGNIFICANCECells organize their interior structures as not only membrane-bound organelles but also as membrane-less organelles. Membrane-less organelles, such as stress granules, Cajal bodies, and postsynaptic density, are biomolecular condensates in which many biomolecules are gathered owing to their interactions. In some cases, biomolecular condensates are formed by tandemly connected multidomain proteins. In such cases, a mesoscopic simulation model representing each domain as a particle is effective; however, the problem with this approach is that a domain-domain pairwise interaction cannot regulate the well-defined valency. To overcome this problem, in this study, we have developed a new potential, viz. the stoichiometric interaction potential, and confirmed that this potential can reproduce the liquid-liquid phase separation of multidomain proteins, a hallmark of the membrane-less organelles.