Current and Incipient Research Projects

Physics of Intracellular Transport

Fluid dynamics, mechanics, and organization of active transport in eukaryotes

Eukaryotic cells must transport components ranging from small molecules to micron-sized vesicles through a complex and heterogeneous physical environment. To aid in this task they employ active transport -- the directed motion of motors along cytoskeletal highways to carry vesicular cargo. While some cargoes are linked directly to molecular motors, others "hitch-hike" by indirect attachment to other vesicles. Some maintain a high affinity for microtubules, lying in wait for attachment to a passing motor, while others undergo diffusion, driven by thermal or actively generated fluctuations that aid in dispersion in between active motion events. We are investigating the mechanics and dynamics of these transport processes, using a combination of simulations and analytical theory for multi-modal transport phenomena, working in collaboration with experimental researchers who track vesicle motion in live cells. Topics of interest include: the role of hydrodynamic entrainment by passing cargoes, the mechanics of attachment by hitchiking cargo, and the efficiency of dispersion by multi-modal transport mechanisms at whole-cell scales.

Mechanics of Active Cytoskeletal Networks

Statistical mechanics of semiflexible networks subject to active remodelling

The large-scale mechanical properties of eukaryotic cells are primarily determined by the cytoskeleton, a cross-linked network of semiflexible filaments that gives the cell rigidity, enables it to move, and allows it to respond to mechanical signals. The actin cytoskeleton forms highly dynamic structures with rapid filament turnover and reversible cross-linking regulated by enzymatic cofactors that enable this network to be exquisitely sensitive to external stimuli. While the mechanical properties of semiflexible polymer networks have been extensively studied in the polymer physics community, the role of dynamic effects unique to biological systems is just now beginning to be explored. We are investigating the behavior of cross-linked networks of semiflexible filaments that are subject to the action of enzymes that actively tug on the cytoskeleton and ones that trigger filament severing or filament growth. Because these enzymes are themselves known to be sensitive to local fiber mechanics and fluctuations, their presence can allow the cytoskeleton to greatly amplify chemical and mechanical signals, triggering large cellular-scale rearrangements in response to specific perturbations. We use coarse-grained analytical models for the statistical mechanics of semiflexible filaments to explore filament dynamics, fracture, and growth in the presence of remodeling enzymes.

Peripheral ER morphology. Figure from: Pukha, et. al., J. Cell Biol., 2007

Reaction Kinetics in Confined Environments

Dynamics of protein interaction and transport within and around organelles

The organelles of eukaryotic cells confine biomolecules within convoluted nanoscale compartments, drastically altering their mixing and transport. A notable example is the endoplasmic reticulum (ER), which forms a dynamic interconnected network of narrow tubules that serves as the site of synthesis for lipids and secretory proteins. The ER plays a key role in protein quality control, with accumulation and aggregation of misfolded proteins triggering key biochemical pathways that instruct the cell to halt further protein synthesis. Because the internal dimensions of ER tubules are of comparable size scale to individual proteins, this organelle provides a highly confined environment for protein interaction. We are exploring the behavior of biochemical reaction networks within a random network of dynamics tubutles, using hybrid Monte Carlo and Brownian dynamics techniques. Key questions of interest include the dynamics of activation of the unfolded protein response pathway, which is believed to function as an all-or-nothing phase transition in response to accumulation of misfolded proteins, due specifically to the effectively one-dimensional nature of the intra-ER environment. Additional questions include the role of extensive organelles such as the ER in cytoplasmic transport, where micron-sized vesicle must maneuver around dynamic membranous structures that occupy more than 10% of cell volume.