Discrete nanoscale transport: Theories, simulations and applications

The present thesis addresses a specific class of transport processes inside cells, namely, those involving nanoscale (10-100 nm) entities, including cellular organelles (e.g. mitochondria, vesicles), pathogens (e.g. viruses) and synthetic materials (e.g. drug and gene carriers). Transport of these nanoscale objects is determined not only by thermal mobility, but also by their interactions with cellular structures, molecular-scale entities, and other nanoscale entities. The complex and multi-scale nature of these interactions has made understanding and prediction of nanoscale transport phenomena tremendously difficult.;In this thesis, we built the theoretical foundation for describing nanoscale transport phenomena in cells. At the heart of the theory is a framework that describes various "transport states" occupied by nanoscale entities. Based on this description, we develop computational models to capture the "flow" of nanoscale entities inside cells. The models, ranging from averaged advection-diffusion-reaction equations to whole-cell stochastic simulations, provide the much needed "spatial view" of cells that is lacking from the current paradigm of systems biology.;We first employed this approach to study organization of intracellular organelles. We showed that cells modulate motor-assisted transport and clustering of organelles to achieve desired intracellular patterns. The patterns predicted by the models agree well with experimental observations. We then performed an in-depth analysis of prominent problems in intracellular transport, including (a) microtubule-dependent transport of endosomes, (b) melanosome dispersion and aggregation in melanophores, and (c) clustering and fusion of lysosomes. The general goal of these studies was to establish a quantitative relationship between molecular scale interactions, the spatial organization emerged from these interactions, and the functionality of the organization.;We also applied the same methodology to study intracellular trafficking of nanoscale drug and gene carriers, in particular, viruses (adenoviruses) and synthetic vectors (PEI-DNA complexes). The model highlighted the effects of several cell-specific properties such as topology (size, circularity and dimensionality) on the transfection efficiency of synthetic vectors. The model provides a platform for integrating experimental information at various length and time scales, building and testing hypotheses and developing a better understanding of the processes involved in intracellular drug delivery.