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.