Theoretical Perspectives on Cellular Compartmentalization by Phase Separation*

Compartmentalization is essential for many cellular functions. Besides organelles encapsulated by lipid membranes—mitochondria and the nucleus, e.g., dynamic non-membrane-bound compartments also exist in the eukaryotic cell. These include stress granules, germ granules, the nucleolus, and many others. Recent investigations indicate that these bodies behave like mesoscopic liquid droplets. Referred to as “membraneless organelles”, or “biomolecular condensates”, they are underpinned to a significant extent by liquid-liquid phase separation (LLPS) of intrinsically disordered proteins (IDPs) and nucleic acids. Their formation/dissolution is governed largely by the information encoded in the sequences of nucleic acids and proteins. To gain physical insights into this novel phenomenon, we developed analytical theories^1-3 and simulation models^4,5 for sequence-specific IDP LLPS. Our effort rationalizes experiments on the DEAD-box RNA helicase Ddx4, elucidates the effect of sequence charge patterns on LLPS⁶, and points to a “fuzzy” mode of molecular recognition by charge pattern matching that likely bears on whether different IDP species remain miscible or demix upon LLPS to serve their biological functions⁷. IDP LLPSs depends on temperature and hydrostatic pressure⁸. As a first step toward understanding these behaviors, we show that the trend of such dependence can be qualitatively rationalized by empirical³ and atomic^9,10 modeling of elementary hydrophobic interactions.

1. Lin, Forman-Kay & Chan, Phys Rev Lett 117:178101 (2016)
2. Lin et al., J Mol Liq 228:176 (2017)
3. Lin, Forman-Kay & Chan, Biochemistry 57:2499 (2018)
4. Das et al., J Phys Chem B 122:5418 (2018)
5. Das et al., q-bio-arXiv:1808.10023 (2018)
6. Lin & Chan, Biophys J 112:2043 (2017)
7. Lin et al., New J Phys 19:115003 (2017)
8. Cinar et al., Chem Eur J 24:8286 (2018)
9. Krobath, Chen & Chan, Biochemistry 55:6269 (2016)
10. Dias & Chan, J Phys Chem B 118:7488 (2014)