Structure and Properties of Cell Membranes Modulated by Membrane-Actin Cytoskeleton Interactions: a Multiscale Computational Investigation

This project aims to computationally investigate the interactions between the cell membrane and the actin cytoskeleton at multiple time and length scales. It will provide critical knowledge for understanding the membrane-cytoskeleton related cellular processes and functions, some of which are key pathogenic factors in a number of human diseases.Considered as a cooperative unit, the membrane–cytoskeleton system is essential for a cell to maintain its functionality. They collaboratively participate in cellular processes such as signal transduction, cell division, and cell migration. They also play important roles in viral entry, assembly, and budding. Loss of membrane-cytoskeleton connections can result in membrane blebbing, hereditary spherocytosis, and even cell death. It is therefore important to understand the mutual interactions and regulations between the membrane and cytoskeleton. Yet, a comprehensive model that describes these interactions is still lacking due to the complexity of their structural interconnectedness.In this proposed research, the PI will computationally investigate (1) at the nanometer scale the interactions between the cell membrane and the actin cytoskeleton, and (2) at the micrometer scale the influence of actin cytoskeleton on the lateral organization and properties of the cell membrane. To achieve this challenging multi-scale computational goal, the PI proposes a three-tier computational approach, where the minimal representation of the cell membrane-cytoskeleton system, i.e. the lipid membrane-actin filament system, will be examined. Firstly, the membrane-actin filament system of hundreds of nanometers will be simulated using coarse-grained molecular dynamics simulations on a microsecond scale. Subsequently, the membrane-actin filament interactions will be quantified using coarse-graining methods. Lastly, the system will be scaled up to a micrometer length scale to examine the structure and dynamics of membranes on top of a dynamic actin filament network at a millisecond time scale.The multi-scale computational approach enables systematic investigation of the membrane-actin filament interactions and the effects of such interactions on the structure and properties of the membrane. The results will provide new insight into the cooperativity of cell membrane and actin cytoskeleton in various cellular processes. From the computational point of view, this proposed work represents the first attempt to place a membrane and actin filaments in the same computational ensemble. Successful completion of this project will generate a new methodology for exploring large and complex biological systems.