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. The goal of this study is to explain how eukaryotic cells move by determining the mechanism by which actin polymerization produces force. To reconsitute the minimal actin-based force generation system requires four components: Arp2/3 complex, actin, capping protein and an Arp2/3 activator on the surface to be pushed. The biochemical properties of these components are well known and the question `What are the possible ways these proteins could come together to produce force?' has yielded multiple models e.g.~elasticity on sub-microscopic scale; elasticity on the mesoscopic scale; filament tethering and pushing; and squeezing. Since the system is underdetermined, the data we have does not eliminate any model nor distinguish the relative contributions of these different mechanisms to motility. The next key question, then, is: 'What are the critical properties of the system that are required to produce the observed motility?' e.g. is network elasticity required? or autocatalysis of polymerication? In this study, by systematically introducing the known properties of the actin system into a computer model, we will determine the specific requirements and contributions of these properties to force production. In the past few months we have generated a Monte Carlo based model that simulates the elastic and compressive properties of an actin network and determine whether mesoscopic elastic properties alone produce symmetry breaking and sustained force as experimentally observed. The next steps are to systematically introduce known properties of the system to evoke the spectrum of observed behaviour, determine their importance and redundancy, and design and conduct experiments to verify the model. Update (Apr 2006): The first pass of the computational side of the project is close to complete, and I have begun writing the first paper from this project, for submission in the next couple of months.
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