Project Summary Membrane targeting and remodeling is 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 the nanoscopic to the mesoscopic time and length scales. For instance, the molecular-level interactions between collections of proteins and the lipid bilayer can have a profound effect on the large scale membrane morphology. 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 and emergent behavior at the mesoscopic level. This project therefore involves the continued development and application of novel multiscale computational methods that are ideally suited to investigate the collective interactions of proteins with membranes. There are two main components of this research: (1) the development of new multiscale simulation methods that can be utilized to study increasingly complex aspects of large scale protein-mediated membrane processes, and (2) the elaboration of the mechanisms by which key proteins target and remodel biological membranes. Three classes of protein-membrane systems will be studied: peripheral membrane proteins (the BAR domain family and how they remodel membranes), transmembrane proteins (influenza M2 protein and how it interacts with the membrane to generate membrane curvature in the course of viral budding), and signaling proteins (PKC, PDK1, and AKT1) to help elucidate the events that take place in the course of the membrane targeting and association by these proteins. The overarching long term goal of this research is to continue to develop and apply a powerful and systematic multiscale computational approach in the study of realistic protein-mediated membrane phenomena.