STOCHASTIC BIOCHEMICAL SIMULATION OF ACTIN-BASED FIBROBLAST CELL SPREADING

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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. Cell motility plays important roles in many physiological processes. Actin-based cell motility is one of the mechanisms that drive cell movement, cell migration and cell morphology in response to extracellular and intracellular signals. Our collaborators, Professor Michael Sheetz and his colleagues at Columbia University, have recently developed quantitative imaging approaches to measure the spreading of mammalian fibroblast cells when they contact extracellular matrix proteins such as fibronectin (Dubin-Thaler, et al Biophys. J. 2004, 86: 1794-1806). We have developed a computational method to model this process in order to understand how cellular signals regulate cell spreading through the motility machinery based on actin cytoskeleton. The goal of this project is to understand whether the signal-regulated and actin-based biochemical reactions that describe the regulated assembly and disassembly of actin filament networks can be used to obtain the quantitative model of cell spreading. We use a stochastic approach to simulate the dynamic growth of actin cytoskeleton which pushes cell membrane forward and results in cell spreading. The main algorithm of our computer simulation program is based on Gillespie's First Method of stochastic simulation of biochemical reactions. The biochemical reactions involved in the simulation of actin-based cell spreading process include actin filament polymerization, actin filament branching and actin filament capping. The growth of actin cytoskeleton based on these biochemical reactions and the movement of cell membrane caused by cytoskeleton growth are simulated in details. Within each loop of Monte Carlo simulation, every actin filament is subject to the calculation of the rates of three actin-based biochemical reactions and the probability distribution based on all reaction rates is sampled to determine which reaction to occur at next step. During this simulation, more and more actin filaments are created as cell keeps spreading, and based on the input molecular concentrations, the number of actin filaments can reach more than 50,000. Therefore the simulation of actin-based cell spreading needs significant amount of computing power to be able to reach biologically meaningful time duration of cell spreading, usually about 2 to 3 minutes. Figure 1 illustrates the stochastic algorithm used by the simulation program. The simulation program has been developed using C++ program language, compiled by GCC 3.4, and tested in Redhat Enterprise Linux 4 in both Intel Pentium4 platform and Intel Itanium2 platform. Based on the nature of this simulation, we need to apply for a Development (Expedited) Allocation on TeraGrid SDSC IA64 Linux Cluster. Since Development Allocation allows up to 30,000 Service Units, We plan to use 48 nodes (96 Itanium2 processors) for 13 days to run our simulation. We can access the TeraGrid using SecureShell connection directly to transfer source and data files and perform command line work.