The onset of whole-cell modeling using the martini force field

Molecular dynamics (MD) is a well established simulation method, which has successfully been applied to study a wide range of biomolecular processes. Continuous improvements in both computational infrastructure and modelling methods have enabled scientists to study mesoscopic, multi-component systems using MD simulations. Understanding how biomolecular functions emerge from millions of interacting molecules is viewed as the next research objective. Since biomolecular processes function on a hierarchy of interconnected scales, decoding the complexity of cellular environments requires us to study them as a whole. We present our ongoing effort to construct a whole-cell model at a molecular resolution, using the Martini coarse-grained force field. We focus our efforts on modeling a genetically minimal cell: the JCVI-syn3A. This cell is engineered to have minimal complexity, making it an ideal starting point for this project. The cell's structural organization and composition is gathered in an integrative modeling approach, combining experimentally resolved data and stochastic lattice model simulations of the whole cell. Incorporating the necessary data into our MD model requires specialized tools, which will be part of the Martini3 ecosystem. The first version of our whole-cell model is presented, showing that performing MD simulations at this scale is feasible. Despite simplifying the cell composition in some key components, this model will provide a starting point for further improvements and pushing the boundaries of realistic whole-cell modeling. Computational microscopy of entire cells and cell organelles will provide valuable insights in a wide range of problems, ranging from drug design to understanding the internal organization of the cellular environments.