Random-phase-approximation theory for sequence-dependent, biologically functional liquid-liquid phase separation of intrinsically disordered proteins

摘要

Intrinsically disordered proteins (IDPs) are typically low innonpolar/hydrophobic but relatively high in polar, charged, and aromatic aminoacid compositions. Some IDPs undergo liquid-liquid phase separation in theaqueous milieu of the living cell. The resulting phase with enhanced IDPconcentration can function as a major component of membraneless organellesthat, by creating their own IDP-rich microenvironments, stimulate criticalbiological functions. IDP phase behaviors are governed by their amino acidsequences. To make progress in understanding this sequence-phase relationship,we report further advances in a recently introduced application ofrandom-phase-approximation (RPA) heteropolymer theory to account forsequence-specific electrostatics in IDP phase separation. Here we examinecomputed variations in phase behavior with respect to block length and chargedensity of model polyampholytes of alternating equal-length charge blocks togain insight into trends observed in IDP phase separation. As a real-lifeexample, the theory is applied to rationalize/predict binodal and spinodalphase behaviors of the 236-residue N-terminal disordered region of RNA helicaseDdx4 and its charge-scrambled mutant for which experimental data are available.Fundamental differences are noted between the phase diagrams predicted by RPAand those predicted by mean-field Flory-Huggins andOverbeek-Voorn/Debye-H\"uckel theories. In the RPA context, a physicallyplausible dependence of relative permittivity on protein concentration canproduce a cooperative effect in favor of IDP-IDP attraction and thus asignificant increased tendency to phase separate. Ramifications of thesefindings for future development of IDP phase separation theory are discussed.