SIMCROST: A Simulator for Understanding the Spatial Regulation in Cross‐Membrane Signal Transduction

Cross-membrane signal transduction is the initial step in cell-signaling pathways that enable responses to specific stimuli. It is not a stochastic event but a highly coordinated process that unfolds through multiple layers of spatiotemporal regulation. The detailed molecular mechanisms and functional implications of these regulations during cross-membrane signal transduction, however, are not completely understood. To tackle this problem, we present a hybrid simulation method called SIMulator of CROss-membrane Signal Transduction (SIMCROST) that incorporates both spatial diffusions of proteins and the kinetics of their interactions to mimic the process ranging from ligand-receptor interactions on the plasma membrane to the assembly of scaffold proteins in the cytoplasm. We tested SIMCROST on a hypothetical system, using currently available experimental evidence of receptor tyrosine kinase (RTK) as a prototype. Our simulation results validate SIMCROST as a powerful tool for elucidating how structural patterns and spatial dynamics regulate physiological cellular responses, providing a mechanistic explanation for previous experimental observations regarding the nonstochastic nature of signal transduction. Moreover, SIMCROST can be potentially applied to any system of cell-signaling pathways and serve as a useful addition to current experimental approaches.