Modeling phase separation dynamics of SynGAP and PSD-95 in postsynaptic densities

Abstract

SynGAP and PSD-95 undergo liquid-liquid phase separation in vitro, motivating models of the postsynaptic density (PSD) as a biomolecular condensate. However, how their association kinetics and intermolecular interactions shape activity-dependent partitioning remains unclear. We develop a multicomponent framework that couples equilibrium Flory-Huggins calculations in conserved total-composition space to four-species Cahn-Hilliard-reaction dynamics for free SynGAP, free PSD-95, the SynGAP-PSD-95 complex, and solvent. Complex formation and dissociation are represented by explicit forward and reverse activity-based mass-action rates. These calculations show that the equilibrium association constant and self- and cross-interaction energies jointly control the extent and composition of the two-phase region. For an illustrative LTP-like parameter switch, decreasing the equilibrium association constant and altering selected interaction energies redistributes SynGAP from the PSD-95-rich phase to the PSD-95-poor phase without eliminating the PSD-95-rich phase. A separate equilibrium comparison represents haploinsufficiency as a 50% reduction in total SynGAP. For the illustrative parameter sets, the reduced-SynGAP composition remains within the two-phase region but has different tie-line endpoints and phase compositions than the control composition.