Comparative roles of charge, π , and hydrophobic interactions in sequence-dependent phase separation of intrinsically disordered proteins

• DOI: 10.1073/pnas.2008122117
• Publication Date: 2020-11-03T01:32:20Z
• Authors: Suman Das; Yi-Hsuan Lin; Robert M. Vernon; Julie D. Forman-Kay; Hue Sun Chan
• Keywords: Intrinsically Disordered Proteins; Globular protein; Electrostatics; Hydrophobic effect

Endeavoring toward a transferable, predictive coarse-grained explicit-chain model for biomolecular condensates underlain by liquid-liquid phase separation (LLPS), we conducted multiple-chain simulations of the N-terminal intrinsically disordered region (IDR) DEAD-box helicase Ddx4, as test case, to assess roles electrostatic, hydrophobic, cation-$\pi$, and aromatic interactions in amino acid sequence-dependent LLPS. We evaluated 3 residue-residue interaction schemes with shared electrostatic potential. Neither common hydrophobicity scheme nor one augmented arginine/lysine-aromatic cation-$\pi$ consistently accounted experimental LLPS data on wildtype, charge-scrambled, an FtoA, RtoK mutant Ddx4 IDR. In contrast, based contact statistics among folded globular protein structures reproduce overall trend, including that has much diminished propensity. Consistency between simulation experiment was also found mutants P-granule LAF-1, underscoring that, degree, important LLPS-driving $\pi$-related are embodied classical statistical potentials. Further elucidation will be necessary, however, especially phenylalanine's role condensate assembly because experiments FtoA YtoF suggest phenylalanine significantly weaker than those posited Protein-protein modulated relative permittivity, which depends concentration. Analytical theory suggests this dependence entails enhanced inter-protein condensed but more favorable protein-solvent dilute phase. The opposing trends lead modest impact