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.
This project concerns the development and application of multiscale computer simulation methods to study the targeting and remodeling of biomembranes by proteins. The specific systems to be studied have been implicated in centronuclear myopathy, paraneoplastic Stiff- Man syndrome in breast cancer, Alzheimer's disease, cell invasion by cancer, cancer cell signaling, and influenza virus budding.
|Madsen, Jesper J; Grime, John M A; Rossman, Jeremy S et al. (2018) Entropic forces drive clustering and spatial localization of influenza A M2 during viral budding. Proc Natl Acad Sci U S A 115:E8595-E8603|
|Simunovic, Mijo; Bassereau, Patricia; Voth, Gregory A (2018) Organizing membrane-curving proteins: the emerging dynamical picture. Curr Opin Struct Biol 51:99-105|
|Simunovic, Mijo; Manneville, Jean-Baptiste; Renard, Henri-François et al. (2017) Friction Mediates Scission of Tubular Membranes Scaffolded by BAR Proteins. Cell 170:172-184.e11|
|Simunovic, Mijo; Šari?, An?ela; Henderson, J Michael et al. (2017) Long-Range Organization of Membrane-Curving Proteins. ACS Cent Sci 3:1246-1253|
|Davtyan, Aram; Simunovic, Mijo; Voth, Gregory A (2017) The mesoscopic membrane with proteins (MesM-P) model. J Chem Phys 147:044101|
|Simunovic, Mijo; Evergren, Emma; Golushko, Ivan et al. (2016) How curvature-generating proteins build scaffolds on membrane nanotubes. Proc Natl Acad Sci U S A 113:11226-11231|
|Davtyan, Aram; Simunovic, Mijo; Voth, Gregory A (2016) Multiscale simulations of protein-facilitated membrane remodeling. J Struct Biol 196:57-63|
|Simunovic, Mijo; Voth, Gregory A (2015) Membrane tension controls the assembly of curvature-generating proteins. Nat Commun 6:7219|
|Simunovic, Mijo; Voth, Gregory A; Callan-Jones, Andrew et al. (2015) When Physics Takes Over: BAR Proteins and Membrane Curvature. Trends Cell Biol 25:780-792|
|Li, Jianing; Ziemba, Brian P; Falke, Joseph J et al. (2014) Interactions of protein kinase C-? C1A and C1B domains with membranes: a combined computational and experimental study. J Am Chem Soc 136:11757-66|
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