Multiscale Simulation of Key Biomolecular Processes in the Cell - PROJECT SUMMARY Biological membranes, protein-protein interactions, and membrane targeting and remodeling by proteins are intimately associated with many critical cellular phenomena, including endocytosis, immune response, organelle formation, cell division, signaling, and movement. These processes are inherently multiscale, as they span from the molecular to nanoscopic to mesoscopic time and length scales. For instance, the molecular-level interactions between collections of proteins and the lipid membrane can have a profound effect on the large scale membrane morphology. Likewise, the atomistic details of actin and actin-binding protein interactions propagate to much longer length and time scales involving protein assembly processes in the cellular cytoskeleton. The interactions of cytoskeleton proteins with membranes are key to many phenomena, including cellular adhesions and motility. Therefore, the main scientific premise of this project is that it is critical to study, in an integrated and coupled fashion, the propagation of local molecular interactions upward in scale to the collective behavior at the cellular level. This research also involves the ongoing development and application of novel multiscale, coarse-grained (CG) computational methods that are ideally suited to investigate the collective interactions of proteins with other proteins and with membranes, including details about conformational states and reactive systems, within the context of key cellular phenomena. There are three main overarching themes of this research that involve the study of increasingly complex aspects of large scale protein-protein complex formations and protein-mediated membrane remodeling processes. These are: (1) employ bottom-up CG models to study realistic membrane systems including peripheral membrane proteins, (2) study the mechanism of large-scale formation and remodeling of actin-based networks as mediated by interactions with actin-binding proteins, and (3) elucidating the mechanisms of protein- mediated remodeling of membranes involved in cellular processes such as the formation of micron-size structures like filopodia and lamellipodia, topological changes such as endocytosis, and dynamic processes such as cell migration with continuous actin turnover. In collaboration with leading experimental researchers to both confirm simulation predictions and to validate the simulation-generated hypotheses, the overarching long- term goal of this research is to continue to apply powerful and systematic multiscale computational approaches to the study of realistic biomolecular processes underlying various important cellular phenomena. These phenomena range from specific interactions at the molecular scale to the concerted action of thousands of proteins.
