(231c) Molecular Insights into Protein Liquid-Liquid Phase Separation from Simulation and Experiment

Authors: 
Dignon, G. L., Lehigh University
Murthy, A. C., Brown University
Conicella, A. E., Brown University
Fawzi, N., Brown University
Mittal, J., Lehigh University
Zerze, G. H., Princeton University
The use of phase separation within the cell accomplishes many important tasks for regular physiological function. This phase separation is highly tunable, and regulated by many external stimuli, and is commonly driven by proteins containing intrinsically disordered regions. We use all-atom explicit solvent simulations of intrinsically disordered proteins (IDPs) to get a detailed view of the intermolecular interactions responsible for stabilizing these highly concentrated proteinaceous phases. We identify the different interaction modes contributing to self-association for two proteins having considerably different amino acid composition, and focus on what different interaction modes, are most prominent. We find that for the disordered domain of RNA-binding protein Fused in sarcoma (FUS) phase separation is driven by promiscuous interactions between many amino acid types[1]. We also consider the effects of helical content on the ability of TDP-43 to phase separate, using rationally-designed mutations to significantly perturb the mechanistic and functional properties of phase-separated assemblies[2].

  1. Murthy, A.C.; Dignon, G.L.; et al. Characterization of the molecular interactions underlying liquid phase separation of the low complexity domain of FUS, (under review).
  2. Conicella, A.E.; Dignon, G.L.; et al. TDP-43 α-helical structure tunes liquid-liquid phase separation and function (submitted).