Designer protein assemblies with tunable phase diagrams in living cells

Until a few years ago it was believed that the internal organisation of the cells was solely due to the presence of organelles separated from the rest of the cytoplasm by membranes. Quite surprisingly, recent advances have shown that there exist a number of organelles, also called biomolecular condensates, that have no membrane and play an important role in the cellular homeostasis. Moreover, the mechanisms underlying the formation of these organelles, mainly composed of proteins and nucleic acids, seem to be also involved in the pathogenesis of diseases caused by abnormal aggregation of proteins such as Alzheimer's, ALS and frontotemporal dementia. Due to the high number of cytoplasm components, identifying the mechanisms that control the formation and dissolution of biomolecular condensates under physiological conditions is very difficult. To overcome this problem, we genetically engineer yeast cells to produce proteins capable of forming biomolecular condensates with controllable chemo-physical properties through self-assembly. We then use molecular dynamics simulations of model systems to (i) draw numerical and theoretical phase diagrams of the experimental synthetic protein system and (ii) investigate the out-of-equilibrium effects as seen in growing cells. Notwithstanding the simplicity of the models we use, which neglect the presence of the solvent and of other macromolecules interacting non-specifically with the synthetic proteins, we are able to capture the essence of the physics of the experimental system, qualitatively reproducing all the trends observed in vivo.

Heidenreich, M., Georgeson, J.M., Locatelli, E. et al. Designer protein assemblies with tunable phase diagrams in living cells. Nat. Chem. Biol. (2020). https://doi.org/10.1038/s41589-020-0576-z