The living cell represents a spatially complex and highly regulated arrangement of molecules whose coordinated motions and activities underlie all the processes within the cells allowing them to grow, reproduce, and carry out a wide spectrum of diverse cellular functions. Along with an increasing number of experimental techniques targeting the identi?cation of the position of subcellular organelles, ribosomes, and macromolecules such as proteins, mRNA, and DNA, there is a growing demand for the next generation of computational tools that allow researchers to construct realistic, cellular-scale structural models at a range of resolutions, to resolve molecular functional states, and to simulate their stochastic, time-dependent behavior in both healthy and diseased cells. The Whole Cell Simulation TRD (TRD3) focuses on a number of software and methodological developments that seek to enable the modeling and simulation of cellular-scale systems. The Center will develop and extend software tools in four complementary modeling areas in cell biology that cover several orders of magnitude in length and time scales: The Molecular Dynamics Flexible Fitting (MDFF) tool enables structural modeling and analysis of large macromolecular assemblies in various functional states through the use of multimodal data, including cryo-electron microscopy (cryo-EM). The future focus of MDFF resides in incorporating advanced simulation methods in an automated fashion to overcome the challenges posed by complex molecular systems, particularly those involving the increasingly obtainable high-resolution cryo-EM data. The Cellular Membrane Modeling (CMM) tools will facilitate model building, simulation, and analysis of com- plex, cellular-scale membrane structures and processes. Technical development will focus on methods and software for constructing realistic membrane models of cells and cellular organelles ( e.g., mitochondria or endoplasmic retic- ulum) with realistic lipid/protein compositions based on experimental data, e?cient embedding of proteins into membrane models, and dynamic reshaping of membrane structures during simulation. The Atomic Resolution Brownian Dynamics (ARBD) tools support simulations of micrometer-scale systems of interacting biomolecules (e.g., the binding of a drug to a ribosome or a signalling cascade leading to cell death) at millisecond and greater time scales. Future work will focus on leveraging GPU technology to speed up simulations, developing tools to construct, visualize, and share BD models, and methods for incorporating chemical reactivity into BD simulations. The GPU-based Lattice Microbes (LM) suite of systems biology simulation tools integrates data from super- resolution imaging, cryo-electron tomography, and -omics experiments into stochastic simulations of reaction di?usion processes in bacterial and eukaryotic cells and colonies over biologically relevant time (hours) and length (m to mm) scales. Future developments will increase the size and complexity of the models LM can simulate, and facilitate the incorporation of more diverse sets of experimental data during model design and analysis.
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