Stochastic Simulation Of Excitation-contraction Coupling

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SUMMARY OF WORK We have begun devoting more attention to so-called spontaneous calcium release events, which vary morphologically from single sparks to localized wavelets to global calcium waves. These events have been shown to play a critical "clock" role in controlling rate in pacemaker cells, as well as triggering arhythmias under pathological condition. In order to model this process, we are constructing a cluster-based thre dimensional stochastic reaction diffusion model describing the dynamics of calcium release channel clusters embedded in a finite-element network in which calcium can diffuse and undergo buffering reactions. Hardware for a dedicated beyowulf cluster (48 processors) has just been delivered and is being installed. Simultaneously, we have successfully ported our previous Monte Carlo excitation-contraction simulation code to the NIH Biowulf computing cluster, parallelized on up to 160 processors. This makes it possible to explore the parameter dependence of the local control model, which is leading to new insights about the mechanism of gain regulation. The parallelized model will form the basis for the extensive software development required to include the three dimensional propagation of calcium release. Even with the new hardware, doing this computation in tractable time will require special progamming methods. We have developed a specialized method for integrating reacdtion diffusion equations that takes advantage of the structure of the biophysical equations to run 100 times faster than a conventional partial-differential equation package. We have recently invented a hierarchical integration scheme in which the differential equation solver calls itself recursively in order to use smaller time steps in regions closer to the calcium sources while taking large steps in the open spaces that constitute most of the volume of the cytosol. These methods are now being coded in Fortran for the two clusters. At the same time, we are collecting extensive experimental data on the statistical properties of calcium release events in cardiac myocytes, for comparison with the output of the 3D stochastic simulation model when the latter is ready to run.