SynGAP and PSD-95 Phase Separation
The postsynaptic density (PSD) is a protein-rich assembly that helps organize signalling at excitatory synapses. SynGAP and PSD-95 can form condensates through liquid–liquid phase separation in vitro, providing a tractable system for asking how molecular interactions organize synaptic proteins. With graduate student Sarah Sakly and collaborator Jennifer Bestman, I am developing mathematical and experimental approaches to connect this molecular organization with synaptic remodelling and dendritic development.
Binding and phase separation
With Sarah Sakly, I have developed a multicomponent model that represents free SynGAP, free PSD-95, their reversible complex and solvent. We combine Flory–Huggins theory for equilibrium mixing with Cahn–Hilliard–reaction dynamics for spatial reorganization and finite-rate association. Phase diagrams describe coexistence and the compositions of the resulting phases; simulations show how the individual species redistribute over time. [1]
The model distinguishes formation of a discrete protein complex from additional effective interactions that favour condensation. This builds on evidence that SynGAP–PSD-95 assembly involves interactions auxiliary to stoichiometric binding. [2] Both association and the other interaction energies influence the extent of the two-phase region and the proteins’ distribution between phases.
In illustrative simulations, weakening association together with selected interaction changes moves SynGAP from the PSD-95-rich phase toward the PSD-95-poor phase while preserving a PSD-95-rich phase. A separate equilibrium comparison reduces total SynGAP by 50%. For the parameter sets considered, two phases still coexist, but their compositions change. These results suggest mechanisms to test; they are not calibrated predictions of phosphorylation, intact synapses or SYNGAP1-associated disorders. The model is described in a bioRxiv preprint currently under revision at Physical Biology. [1]
From molecular assemblies to neuronal development
Our NSF-supported project, Mathematics of membraneless organelles — the postsynaptic density, extends this work through collaboration with Jennifer Bestman. We will investigate how SynGAP isoforms, variants and dosage affect condensate organization, and how those changes relate to dendritic maturation and synaptic function. Planned experiments include purified-protein phase-separation assays, measurements of molecular exchange by fluorescence recovery after photobleaching, and live imaging and electrophysiology in the Xenopus retinotectal system. Theoretical extensions will address multivalent network formation, finite condensate size, membrane geometry and exchange with the surrounding cytosol. These studies aim to connect molecular variation with measurable cellular phenotypes relevant to SYNGAP1-associated neurodevelopmental disorders.
The project also supports interdisciplinary student training and the development of reusable computational tools. NSF award 2619756 supports the work from September 2026 through August 2029.
References and project support
[1] Sakly S, Conradi Smith G (2026). Modeling phase separation dynamics of SynGAP and PSD-95 in postsynaptic densities. bioRxiv preprint. doi:10.64898/2026.07.23.740312.
[2] Lin YH, Wu H, Jia B, Zhang M, Chan HS (2022). Assembly of model postsynaptic densities involves interactions auxiliary to stoichiometric binding. Biophysical Journal 121:157–171. doi:10.1016/j.bpj.2021.10.008.
National Science Foundation. Award 2619756: Mathematics of membraneless organelles — the postsynaptic density. Principal investigator: Gregory D Conradi Smith. Co-principal investigator: Jennifer E Bestman. William & Mary. 1 September 2026–31 August 2029.