Membrane Geometry Regulates Phase Morphology in Postsynaptic Condensates

Biomolecular condensates are generally regarded as membrane-less organelles formed through liquid–liquid phase separation (LLPS). However, some condensates in living cells emerge in close proximity to biological membranes, where spatial confinement and surface geometry can critically influence their organization and function. In this talk, I will discuss recent advances in understanding how membrane association regulates the phase behavior of postsynaptic density (PSD) condensates. Using mesoscale molecular simulations constrained by experimental interaction data, our study reproduced the distinct condensate architectures observed in solution and on membranes. In three-dimensional solution, AMPA receptor/PSD-95 complexes form the condensate core, whereas NMDA receptor/CaMKII complexes localize to the shell. Strikingly, this organization becomes reversed in membrane-associated two-dimensional systems. The analysis revealed that this transition arises from the competition between CaMKII’s large excluded volume and its highly multivalent interactions. While excluded-volume effects dominate in solution, membrane confinement favors specific multivalent interactions, stabilizing distinct receptor nanodomains. These results provide a physical framework for understanding how spatial dimensionality and molecular architecture regulate biomolecular condensates and synaptic organization.