Multiscale Computer Simulation of Key Biomolecular Processes in the Cell

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Project Summary Protein-protein interactions, self-assembly, and membrane targeting and remodeling are intimately associated with many critical cellular phenomena, including endocytosis, infection, immune response, organelle formation, cell division, signaling, and movement. These processes are innately 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. Therefore, the main scientific premise of this project is that it is critical to study, in a coupled fashion across multiple scales, the propagation of local molecular interactions upward in scale to the collective behavior at the cellular level. The research involves the continued development and application of novel multiscale, coarse-grained computational methods that are ideally suited to investigate the collective interactions of proteins with other proteins and with membranes, within the context of key cellular phenomena There are two main overarching aims of this research: (1) the continued development of new multiscale simulation methods that can be utilized to study increasingly complex aspects of large scale protein-protein and protein-mediated membrane processes, and (2) the elaboration of the mechanisms by which key proteins target and remodel realistic biological membranes, and how proteins interact and self-assemble with one another in the cytoskeleton and at the cytoskeleton-membrane interface. In collaboration with leading experimental researchers, the applications of the multiscale simulations will include studies of realistic membrane models, protein-mediated remodeling of membranes and actin filaments, the interaction of actin filaments with peripheral membrane proteins to regulate membrane curvature, and the mechanism of highly ordered coat protein-induced membrane remodeling. The overarching long term goal of this research is to continue to develop and apply a powerful and systematic multiscale computational approach for the study of realistic biomolecular phenomena of significant importance to various cellular phenomena.