Beyond Pairwise: Higher-order physical interactions affect phase separation in multi-component liquids (2403.06666v1)
Abstract: Phase separation, crucial for spatially segregating biomolecules in cells, is well-understood in the simple case of a few components with pairwise interactions. Yet, biological cells challenge the simple picture in at least two ways: First, biomolecules, like proteins and nucleic acids, exhibit complex, higher-order interactions, where a single molecule may interact with multiple others simultaneously. Second, cells comprise a myriad of different components that form various droplets. Such multicomponent phase separation has been studied in the simple case of pairwise interactions, but an analysis of higher-order interactions is lacking. We propose such a theory and study the corresponding phase diagrams numerically. We find that interactions between three components are similar to pairwise interactions, whereas composition-dependent higher-order interactions between two components can oppose phase separation. This surprising result can only be revealed from the equilibrium phase diagrams, implying that the often-used stability analysis of homogeneous states is inadequate to study these systems. We thus show that higher-order interactions could play a crucial role in forming droplets in cells, and their manipulation could offer novel approaches to controlling multicomponent phase separation.
- A. A. Hyman, C. A. Weber, and F. Jülicher, Liquid-liquid phase separation in biology, Annu. Rev. Cell Dev. Biol. 30, 39 (2014).
- F. Jülicher and C. A. Weber, Droplet physics and intracellular phase separation, Annual Review of Condensed Matter Physics 15 (2023).
- P. I. Flory, Thermodynamics of high polymer solutions, The Journal of Chemical Physics, J. Chem. Phys. 10, 51 (1942).
- M. L. Huggins, Solutions of long chain compounds, The Journal of chemical physics 9, 440 (1941).
- D. Zwicker, The intertwined physics of active chemical reactions and phase separation, Current Opinion in Colloid & Interface Science , 101606 (2022).
- G. L. Dignon, R. B. Best, and J. Mittal, Biomolecular phase separation: from molecular driving forces to macroscopic properties, Annual review of physical chemistry 71, 53 (2020).
- M. Doi, Introduction to polymer physics (Oxford university press, 1996).
- G. Fredrickson, The equilibrium theory of inhomogeneous polymers, 134 (Oxford University Press, 2006).
- A. S. Holehouse and B. B. Kragelund, The molecular basis for cellular function of intrinsically disordered protein regions, Nature Reviews Molecular Cell Biology , 1 (2023).
- Y.-H. Lin, J. D. Forman-Kay, and H. S. Chan, Theories for sequence-dependent phase behaviors of biomolecular condensates, Biochemistry 57, 2499 (2018).
- J. Dudowicz, K. F. Freed, and J. F. Douglas, Beyond Flory-Huggins Theory: New Classes of Blend Miscibility Associated with Monomer Structural Asymmetry, Physical Review Letters 88, 095503 (2002).
- A. I. Pesci and K. F. Freed, Lattice theory of polymer blends and liquid mixtures: Beyond the Flory–Huggins approximation, The Journal of Chemical Physics 90, 2017 (1989).
- R. P. Sear, The cytoplasm of living cells: a functional mixture of thousands of components, Journal of Physics: Condensed Matter 17, S3587 (2005).
- W. Bruns, The third osmotic virial coefficient of polymer solutions, Macromolecules 30, 4429 (1997).
- J.-M. Choi, A. S. Holehouse, and R. V. Pappu, Physical principles underlying the complex biology of intracellular phase transitions, Annual review of biophysics 49, 107 (2020).
- T. Idema, J. Van Leeuwen, and C. Storm, Phase coexistence and line tension in ternary lipid systems, Physical Review E 80, 041924 (2009).
- I. Billick and T. J. Case, Higher order interactions in ecological communities: what are they and how can they be detected?, Ecology 75, 1529 (1994).
- M. M. Mayfield and D. B. Stouffer, Higher-order interactions capture unexplained complexity in diverse communities, Nature ecology & evolution 1, 0062 (2017).
- E. Bairey, E. D. Kelsic, and R. Kishony, High-order species interactions shape ecosystem diversity, Nature communications 7, 12285 (2016).
- T. Gibbs, S. A. Levin, and J. M. Levine, Coexistence in diverse communities with higher-order interactions, Proceedings of the National Academy of Sciences 119, e2205063119 (2022).
- V. Thibeault, A. Allard, and P. Desrosiers, The low-rank hypothesis of complex systems, Nature Physics , 1 (2024).
- L. Herron, P. Sartori, and B. Xue, Robust retrieval of dynamic sequences through interaction modulation, PRX Life 1, 023012 (2023).
- W. M. Jacobs, Theory and simulation of multiphase coexistence in biomolecular mixtures, Journal of Chemical Theory and Computation (2023a).
- R. P. Sear and J. Cuesta, Instabilities in complex mixtures with a large number of components., Physical Review Letters, Phys. Rev. Lett. 91, 245701 (2003).
- W. M. Jacobs and D. Frenkel, Phase transitions in biological systems with many components, Biophys. J. 112, 683 (2017).
- K. Shrinivas and M. P. Brenner, Phase separation in fluids with many interacting components, Proc. Natl. Acad. Sci. USA 118, 10.1073/pnas.2108551118 (2021).
- V. Baulin and A. Halperin, Concentration dependence of the flory χ𝜒\chiitalic_χ parameter within two-state models, Macromolecules 35, 6432 (2002).
- D. Zwicker and L. Laan, Evolved interactions stabilize many coexisting phases in multicomponent liquids, Proceedings of the National Academy of Sciences 119, e2201250119 (2022).
- W. M. Jacobs, Theory and simulation of multiphase coexistence in biomolecular mixtures, J. Chem. Theory Comput. 19, 3429 (2023b).
- J. W. Gibbs, On the equilibrium of heterogeneous substances, Transactions of the Connecticut Academy of Arts and Sciences, Trans. Conn. Acad. Arts Sci. 3, 1 (1876).
- F. Chen and W. M. Jacobs, Programmable phase behavior in fluids with designable interactions, The Journal of Chemical Physics 158 (2023).
- F. C. Thewes, M. Krüger, and P. Sollich, Composition dependent instabilities in mixtures with many components, Physical Review Letters 131, 058401 (2023).
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