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Center for Nonlinear Studies |
Many activities of cells are controlled by cell surface receptors, which respond to ligands by triggering intracellular signaling reactions. Improved understanding of receptor signaling has a number of potential practical applications, such as the rational design of drugs and vaccines. The process of signaling through receptors involves highly connected networks of interacting components. Understanding the behavior of these networks requires the development of mathematical and computational modeling. Here, an agent-based simulator is developed to study diverse molecular interactions in complex signaling pathways with spatial resolution and single molecule detail. It permits stochastic modeling of protein clustering, protein motion and biochemical reactions within an idealized cellular geometry. Particles diffuse and react with nearby particles in accord with chemical rate reactions. Reactions occurring between two molecules depend on the specific types of molecules and their physical states. The modularized design confers flexibility. The model was applied to investigate mechanisms of ligand-independent EGFR homodimerization and activation as functions of time and receptor conformation, density and spatial distribution. Results indicate that receptor density is a principal factor in the ability to form a measurable amount of active homodimers in the absence of ligands. Our results also predict that receptor clustering exacerbates the density-dependent homodimerization of unoccupied receptors. Second, we considered the effects of receptor clustering patterns of ErbB family members on hetero- and homo-dimerization rates, using immunoelectron microscopy data derived from the SKBR3 breast cancer cell line that expresses ErbB2>>EGFR>ErbB3. Results show that partial spatial segregation of ErbB receptors has a profound impact on simulated heterodimerization rates. We are poised to proceed with testing the model for interactions of downstream signaling molecules, based in part on spatial constraints of docking partners and on observed patterns of signaling proteins in membranes.
Host: Bill Hlavacek, T-10