Simulating the polymer-mediated phase separation of model proteins with multiple domains

In biology there are many proteins which have been shown to form liquid-like condensates, or 'droplets' within cells. Some of these proteins interact with the genome and drive the regulation of genes; they are thought to play a vital role in cell function. How such droplets are formed, and how their spatial and temporal location are controlled are not yet well understood. Inspired by these systems, we used course grained Langevin dynamics simulations to study the physics of simple model proteins interacting with a polymer (representing the genome). These simulations are reminiscent of the well-studied 'patchy particle' systems in soft matter physics [1], where colloids decorated with 'sticky spots' display a complex phase diagram, which includes liquid, gas, gel, and 'closed loop' phases.  

In this work we focused particularly on the interplay between two different mechanisms which drive phase separation or protein clustering. These are (1) protein self attractions, as in a standard binary fluid phase separating system, and (2) the bridging induced attraction [2,3], when protein-mediated polymer bridging leads to protein clustering. Our simulations reveal a new regime where protein droplets only form due to interaction with the polymer [4]; here, unlike in a standard phase separating system, droplet density rather than size varies with the overall protein concentration. We also observe that protein dynamics within droplets slow down as the polymer is absorbed. Overall, the results from this highly simplified model provide biologically relevant insights into the general nature of protein-chromatin condensates in living cells.

[1] E Zaccarelli "Colloidal gels: equilibrium and non-equilibrium routes"  J. Phys. Condens. Matter 19:323101 (2007)

[2] CA Brackley, S Taylor, A Papantonis, PR Cook, and D Marenduzzo "Nonspecific bridging-induced
attraction drives clustering of DNA-binding proteins and genome organization." Proc. Natl. Acad. Sci. USA 110:E3605–E3611 (2013)

[3] CA Brackley "Polymer compaction and bridging-induced clustering of protein-inspired patchy particles." J Phys. Condens. Matter 32:314002 (2020)

[4] M Ancona and CA Brackley "Simulating the chromatin mediated phase separation of model proteins with multiple domains" arXiv 2107.14518 (2022)

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