Toward Systems Biology

May 30 - 31, June 1, 2011


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Investigating receptor clustering with coarse-grained spatial Monte-Carlo simulations

The initial steps in cell-to-cell signaling involve the binding of (ligand) molecules located outside the cell to receptor molecules confined to the cell membrane, and the subsequent formation of an aggregate or complex that initiates the signaling cascade. Many receptor types exhibit ligand-induced dimerization. Because of their cooperative nature, the initial binding steps are intimately connected to the spatial distribution of membrane receptors.

Modern microscopy has shown that cell membrane proteins and lipids are organized in micro-domains, and that their free movement is hindered, possibly due to interaction with the cytoskeleton. The spatial distribution of many membrane receptors (EGFR, VEGFR, FcεRI) is inhomogeneous, with clusters (high density patches) of a few to hundreds of receptors. The mechanism of receptor clustering is not clear. The presence of ligand enhances receptor clustering, pointing to a possible role for ligand-induced dimerization in the emergence of clusters.

We use spatial Monte-Carlo simulations to investigate the hypothesis of dimerization-induced clustering in microdomains separated by barriers to receptor movement. We model the dimerization and diffusion of receptors in a membrane patch partitioned into domains. Monomers may cross a domain boundary, but with much smaller probability than diffusion in open space; dimer crossing is even more severely limited.

However, we must capture dynamics at length scales comparable to the size of a receptor, but the simulated membrane region must be large enough to include the depleted areas. We developed a a two-prong simulation strategy. We perform microscopic lattice Monte-Carlo simulations covering 1-2 individual domains to derive average barrier crossing (exit) rates, given a number of receptor molecules in a domain. At the coarse-grained level, the membrane is modeled as a network of domains without spatial structure, with well-mixed (Gillespie) kinetics and receptor exit rates derived from the microscopic simulations.

Adam Halasz, University of West Virginia