Mechanistic Modeling of Cellular Systems

Project Summary This proposal aims to continue operation of the National Resource for Mechanistic Modeling of Cellular Systems, to serve the large community of cell and systems biologists. The Resource encompasses the 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. From 2020-2024, the Resource has supported research in 437 publications from a wide array of scientific fields, including metabolism, cell signaling, cancer, aging, chemistry, biophysics, and others. The two software technologies were also used to help develop a variety of new experimental methodologies. This support includes 77 NIH- funded grants. The Resource will continue maintaining the software removing bugs and adapting it to new developments in operating systems, as well as expanding their utility by adding other established methodologies for modeling and simulation. Both VCell and COPASI are hosted at the University of Connecticut School of Medicine and benefit from: (1) the common institutional organization under which they operate; (2) a joint website; (3) a common high performance computing facility that serves the computationally intensive needs of users without charges; (4) coordinated training and outreach to the user community in the form of web-based documentation and tutorials, two yearly Computational Cell Biology Workshops and numerous roadshows at national and international meetings. Additionally, VCell and COPASI are 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 actively engages with the community of researchers defining software standards to assure the reproducibility and reusability of both the software and the models it generates.