Development of Smoldyn

About This Grant

PROJECT SUMMARY / ABSTRACT Modeling and simulation are essential to modern cell biology research, but modeling tools have not kept pace with experimental work. In particular, many of the subcellular structures that are routinely investigated by modern microscopy methods can only be modeled at present with custom software. This is because no general-purpose simulators can simultaneously represent proteins, filaments (e.g. DNA and actin), and membrane dynamics. Such capability is essential for investigating fundamental cellular processes such as transcription, cell division, endocytosis, and cell motility. We will develop the necessary algorithms and implement them in our existing Smoldyn software, a widely used tool that is a leader in the spatial modeling field. One of our algorithm sets will focus on filament dynamics. It will accurately capture bending, twisting, branching, and excluded volume effects for filaments, along with interactions between filaments and both molecules and surfaces. These interactions will support simulation of molecular motors, DNA transcription, and feedback from filament- bound proteins to the filament conformations. Our algorithms will represent filaments at a high level of detail and will simulate efficiently through the use of multiple solvers that are optimized for different parameter options. Another algorithm set will focus on membrane dynamics, such as deformation, endocytosis, and cell division, along with the intracellular interactions that arise in those processes. The resulting simulator will be able to model a wide range of elementary cell biology processes and, by extension, most of the complexity of real cells. Our research team includes members from a lab that combines experimental and theoretical work. They will use our software, as it is developed, to model actin assembly against load from membrane elasticity and actin-driven endocytosis. This portion of the work will help motivate and direct the methods development work because it will use a wide range of our new software features. It will also be important in its own right because it will address open questions about the reciprocal relationships between actin- driven forces, actin architecture, and membrane shape in endocytosis. We will continue to work closely with the broader biochemical modeling community through software support and help with integrating our software into other tools as a back-end physics engine. We will also work with the community in the ongoing development of a standardized language for describing spatial cell biological models. We anticipate that our work will have a high impact in cell biology research because it will enable realistic spatial modeling for systems that cannot be modeled at present with existing tools. Many researchers have directly requested these software features, in person and in letters of support.