Flexible nanofilaments are fundamental components of man-made materials, living cells and of viruses such as Ebola. The importance to human health of nanofilaments is highlighted by the recent outbreak of Ebola virus disease in West Africa, which began in 2013 and continued for over two years. Understanding how nanofilaments enter living cells, therefore, has important relevance to society. This project is aimed to understand how flexible nanofilaments interact and enter human and animal cells, thereby helping address the urgent societal needs to understand the life cycle of filoviruses as well as the potential health hazards of engineered nanomaterials. Results from this research will benefit the U.S. economy and society, as engineered nanomaterials are becoming a significant fraction of material flows in the U.S. and most of the manufactured nanomaterials will eventually end up in landfills, hence impacting our ecosystem and health. The multi-disciplinary approach of the research will positively impact engineering education and outreach activities at Brown University. The educational programs will provide training for graduate students and visiting scholars, as well as research experience for undergraduate students.
This work will address the following fundamental mechanics issues that underlie a vast variety of experimental observations in the field: (1) attachment of flexible nanofilaments onto a cell membrane, (2) fusion of membranes that envelop nanofilaments, (3) biopackaging of flexible nanofilaments, and (4) budding of nanofilaments from a cell membrane. The technical approaches will be based on a number of theoretical and simulation techniques developed by the PIs research group in cell mechanics. This work will provide useful insights into the kinetics of cell processing of nanofilaments through theoretical modeling and large scale coarse-grained molecular dynamics simulations of protein-mediated nucleation of adhesion domains with considerations of receptor diffusion, binding kinetics and membrane undulation, membrane fusion focusing on the effects of size, shape and bending rigidity of enveloped nanofilaments and compositions of lipid membranes, determination of phase diagrams of cell packaging of nanofilaments and filament networks with respect to the length, elastic properties and interaction between nanofilaments and cell membranes, and effects of mechanical properties and cell interactions on modes of nanofilament budding. The ultra-large scale simulations in the work will be performed at the National Institute for Computational Sciences, and the rest of the computational work will be performed at the Center for Computing and Visualization at Brown University.
