Compartmentalization at the cellular and sub-cellular levels is ubiquitous in all life forms as it is essential for biological functions. Recent experimental advances underscore that some of the intra-organismic compartmentalized bodies are devoid of a lipid membrane—unlike a cell or intracellular organelles such as mitochondria. Hence these bodies are sometimes called “membrane-less organelles.” Possessing material properties like those of mesoscopic liquid droplets and collectively referred to as “biomolecular condensates,” their assembly is now widely recognized to be based to a significant degree by liquid-liquid phase separation (LLPS) of intrinsically disordered proteins (IDPs), intrinsically disordered regions (IDRs) of proteins, globular protein domains, and nucleic acids—though other physicochemical processes also contribute. To gain physical insights into their organizing principles, our group has developed analytical theories—these include conventional Flory-Huggins formulations, random phase approximation, Kuhn-length renormalization, and new formulations of field-theoretic simulation as well as coarse-grained explicit-chain molecular dynamics models for sequence-specific LLPS of IDPs/IDRs. This effort has elucidated the effect of sequence charge pattern, π-related interactions, pH, and salt on biomolecular LLPS. Among other findings, our results point to a “fuzzy” mode of molecular recognition by charge pattern matching modulated by chain excluded-volume effects, which should contribute to deciphering how different IDP species may de-mix upon LLPS to achieve functional sub-compartmentalization. A first step has also been taken toward rationalizing the temperature and pressure dependence of LLPS by empirical and atomic models of solvent-mediated hydrophobic interactions and the interplay between stoichiometric and less-specific multivalent interactions in the assembly of biomolecular condensates. Biological ramifications of our findings will be discussed, including a preliminary notion of how the pressure sensitivity of an in vitro model of postsynaptic densities might be related to pressure-related neurological disorders in terrestrial vertebrates.
Webpage of Prof. Chan: http://biochemistry.utoronto.ca/person/hue-sun-chan/
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