TCBG Seminar

Novel Microphysiological Design Principles Predicted from Spatially Realistic Monte Carlo Simulations

Dr. Joel R. Stiles
Director, Center for Quantitative Biological Simulation
Pittsburgh Supercomputing Center
Carnegie Mellon University

Monday, April 24, 2006
3:00 pm (CT)
3269 Beckman Institute


Cells are tightly packed with structures and molecules that carry out the day-to-day operations of living. Understanding how cellular design dictates function is essential to understanding life and disease, in the brain, heart, or elsewhere. The MCell/DReAMM modeling environment is focused on cellular microphysiology, and is under development at the Center for Quantitative Biological Simulation at the Pittsburgh Supercomputing Center and the Computational Neurobiology Laboratory at the Salk Institute. I will introduce new capabilities of MCell and DReAMM, and present a current model of acetylcholine exocytosis and calcium dynamics (nano- and microdomains) at the vertebrate neuromuscular junction. The model is based on a spatially realistic active zone within the nerve terminal, and includes discrete voltage-gated calcium channels, synaptic vesicles, calcium buffers, and sub-vesicular calcium binding sites corresponding to domains on synaptotagmin molecules. The model is constrained by calcium imaging and electrophysiological data, and predicts novel spatiotemporal relationships between calcium channels, calcium ions, synaptic vesicles, and calcium binding sites with independent or cooperative kinetics. These predictions are supported by recent evidence for numbers of SNARE complexes and calcium binding sites per synaptic vesicle, and possible cooperativity of synaptotagmin binding to trigger vesicle fusion (exocytosis). More generally, this project illustrates how spatially realistic microphysiological simulations can elucidate design principles for high sensitivity, fidelity, and adaptability of cellular function.

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