Project Summary This proposal aims to establish a National Resource for Mechanistic Modeling of Cellular Systems to serve the large community of cell and systems biologists. The Resource will encompass COPASI and Virtual Cell (VCell) software platforms, which are arguably the most comprehensive and widely used tools for computational modeling of the biophysical mechanisms controlling cell function. VCell supports a number of key biophysical mechanisms, including reaction kinetics, diffusion, flow, membrane transport, lateral membrane diffusion, electrophysiology and rule-based models of multi-state/multimolecular interactions. Simulations can be based on 0D, 1D, 2D or 3D analytical or experimental image-based geometries. Users may choose among multiple available simulation approaches: ordinary differential equations, partial differential equations, stochastic reaction kinetics, network-free simulations, spatial particle-based simulations and spatial hybrid stochastic/deterministic simulations. COPASI enables the simulation and analysis of complex biochemical reaction networks either deterministically or stochastically. It offers a broad range of analysis tools including parameter estimation/optimization, steady state analysis, stoichiometric analysis, sensitivity analysis and metabolic control analysis. VCell and COPASI each boast thousands of active users. Collectively, their users produce >100 papers per year relying on these software systems. Both VCell and COPASI will be hosted at the University of Connecticut School of Medicine. Thus, the Resource will benefit from: (1) the common institutional organization under which it will operate; (2) a joint website; (3) a common high performance computing facility that will serve the computationally intensive needs of users; (4) coordinated training and outreach to the user community in the form of web-based documentation and tutorials, a yearly Computational Cell Biology Workshop and numerous roadshows at national and international meetings. Additionally, VCell and COPASI will be leveraged by external systems biology software developers as user-friendly platforms for the wide dissemination of their third party algorithms, software and databases. Finally, the Resource will actively engage with the software standards community to assure the reproducibility and reusability of both the software and the models it generates.