(675e) A Multiscale Brownian Dynamics Model Predicts Diffusion-Controlled Multivalent Antigen-Receptor Assembly in the Cell Membrane

Multivalent ligand-receptor assembly is a key feature of many cell signal transduction systems. However, the regulatory mechanisms that govern ligand-receptor assembly in the plasma membrane of a cell remain poorly understood. Current modeling and simulation techniques provide limited capability to mechanistically investigate such systems. A key challenge is to deal with the multiscale nature of the problem. Multivalent molecules may interact via their subnanometer-scale binding features (domains or motifs). On the other hand, membrane diffusion and assembly of macromolecular species might take place at relatively longer time and larger spatial scales. This work presents a multiscale spatiotemporal model of IgE receptor (FceRI) aggregation in the plasma membrane of a mast cell. By employing a time-adaptive Brownian Dynamics simulation, we investigate how membrane diffusion might regulate a trivalent ligand-induced FceRI aggregation. This system has been studied previously by several earlier models, which were developed using the nonspatial approaches. These earlier works predicted that a multivalent ligand may induce very large FceRI aggregate (superaggregate or gel) formation in the cell membrane. These works underscored the possibility that such gel formation might enable cells to generate hyperactive responses. However, recent experimental studies with synthetic trivalent ligands have revealed finite-sized receptor clusters in the cell membrane. Our spatiotemporal model interestingly makes predictions consistent with these experimental findings. We show that membrane diffusion may play a key role in regulating the time-evolving size of the ligand-receptor complexes upon stimulation. Our model underscores the spatiotemporal effects arising from the diffusion and steric hindrance that were missing in the earlier nonspatial models.