Elucidating the Functional Roles of Spatial Organization in Cross-Membrane Signal Transduction by a Hybrid Simulation Method

Abstract

The ligand-binding of membrane receptors on cell surfaces initiates the dynamic process of cross-membrane signal transduction. Recent experiments revealed that molecular components in signal transduction are not randomly mixed, but spatially organized into distinctive patterns that lead to very different gene-expression profiles. However, little is understood about the molecular mechanisms and functional impacts of this spatial-temporal regulation. Here we developed a hybrid computational method that decomposes signaling networks into two simulation modules. The physical process of binding between receptors and ligands are simulated by a diffusion-reaction algorithm, while the downstream biochemical reactions are modeled by stochastic simulation of Gillespie algorithm. Using this method, we tested the dynamics of a simple signaling system. We found that spatial aggregation of membrane receptors is able to either amplify or inhibit downstream signaling outputs, depending on the clustering mechanism. Moreover, by providing higher binding avidity, the co-localization of ligands into multi-valence complex modulates signaling in very different ways that are closely related to the binding affinity between ligand and receptor. We also found that the temporal oscillation of the signaling pathway from genetic feedback loops can be modified by receptors clustering. Our method demonstrates the functional importance of spatial organization in cross-membrane signal transduction.