This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We propose to apply multiscale modeling methods to simulate the spatial self-organization of proteins in the plasma membrane whose disregulation is implicated in hormone-responsive cancers. The specific system of interest is the epidermal growth factor receptor (EGFR). This is one of the most common receptors in living cells that has served as a prototype system for numerous experimental studies. Accumulated experimental evidence, via transmission electron microscopy (TEM) and single particle tracking (SPT) techniques, has clearly established the existence of heterogeneity of the plasma membrane into small microdomains, which are cholesterol rich, dispersed into large domains. It is within these small microdomains where EGFR mainly partitions and upon exposure to an extracellular signal, clustering occurs leading eventually to endocytosis. The proposed work will attempt to analyze available experimental data and provide the much-needed insights into the self-organization of the EGFR. The ultimate objective of this work is to understand the key factors controlling self-organization and clustering of receptors in order to enable their control. We propose to develop suitable coarse-grained molecular models while explicitly accounting for the main constituents of the lipid bilayer and the solvent. These coarse models will be used to study microphase separation to establish the self-aggregation mechanism of the EGFR into different membrane domains and compare simulation results to experimental data.
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