Metastable Biological Matter
Cells compartmentalize to organize a myriad of biomolecules and biochemistry hierarchically, conventionally known to form lipid bilayer membrane-bound organelles 1. Nonetheless,liquid-liquid phase separation (LLPS, see Glossary ) emerges recently as another universal phenomenon for intracellular organization, particularly via the formation of membraneless organelles (MLOs) hosting intrinsically disordered proteins(IDPs) as scaffolds, which have important roles in cellular physiology and disease 2–4. The liquid-like MLOs are biological soft matter that afford multifold peculiarities, including high dynamics, reversibility and environmental responsiveness5. Notably, there is growing evidence that ‘metastability ’ is a universal and pivotal nature of liquid-like MLOs 6. For one thing, MLOs are capable of undergoing fast, drastic and reversible formation and dissolution events commensurate with surrounding intracellular environment7. For another, the liquid state has an inherent tendency to transit into more stable glassy or gel-like states8, simply over time 9 or expedited by disease-associated mutations 10–13. Moreover, the alteration of metastable state has been revealed to be closely tied with cellular physiology and pathology 14, whilst the manipulation of LLPS can be promising route towards effective treatment of diseases 15.
In this review paper, we highlight the ubiquitous yet essential metastability of liquid phase separation of biological soft matter. We first depict the free energy landscape of biological matter, and underscore the metastable state of MLOs with liquidity. We next discuss about the distinctive metastable molecular interactions and molecular structures implicated in liquid-like MLOs. Through examples, we then highlight the metastable material state of biological assemblages formed through liquid phase separation. Lastly, we describe how metastability provides a pivotal link between physiology and disease.