Core--Development of new Features in MCell

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Typical cellular processes occur in highly organized subcellular spaces, where ligand and ligand-binding molecules participate in complex signaling pathways. In general, then, it is not sufficient to consider molecular signals, such as the intracellular Ca 2+ concentration, only in well-mixed whole cell terms, but instead attention must center on the relevant subcellular microdomains. The number of signaling and effector molecules can be quite small, and computers have become powerful enough so that it is now feasible to simulate every important molecule in subcellular regions. MCell is a general computer program designed to simulate microdomains and associated biochemical signaling mechanisms. The specific aims of this core will add new capabilities to MCell that will streamline the process of mapping molecules and macromolecular complexes into realistic three-dimensional reconstructions of cellular ultrastructure and will implement algorithms for simulating interactions between diffusing molecules. The first specific aim is to design algorithms to permit simulation of all possible pair-wise interactions between diffusing molecules, which will allow simulation of cytosolic signal transduction cascades within MCelI. The second specific aim is to develop a user-friendly cellular computer-assisted design (CAD) system for use with the MCell program. The cellular CAD system will allow graphical design of realistic models of neurons and other cell types at the subcellular and molecular level and to rapidly populate surfaces with channels, pumps and other molecules at specified densities. The third specific aim is to design algorithms to streamline the representation of macromolecular complexes and reaction networks. This will involve the development of a high-level and hierarchical representation language for reaction networks that will provide a convenient, machine readable, shorthand for representing complex reaction networks. This proposed MCell development will also allow the user to specify the level of coarse-graining by letting the label structure specifying the internal states of reactants to be defined as needed for specific applications. These new modeling capabilities for MCell are prerequisite for the success of Project 1 (Sejnowski) and Project 3 (Kennedy) in this proposal and will facilitate the integration of experimental data from Project 2 (Weinberg) and Project 4 (Svoboda) into MCell simulations.