Control of Nonequilibrium Self-Assembly in the Cell


In diverse cellular pathways including clathrin-mediated endocytosis (CME) and viral bud formation, cytosolic proteins must self-assemble and induce membrane deformation. To understand the mechanisms whereby assembly is triggered and how perturbations can lead to dysfunction requires dynamics of not just assembly components, but their coupling to active, force-responsive, and ATP-consuming structures in cells. Current computational tools for studying self-assembly dynamics are not feasible for simulating cellular dynamics due to the slow time-scales and the dependence on energy-consuming events such as phosphorylation. We recently developed novel reaction-diffusion algorithms and software that enable detailed computer simulations of nonequilibrium self-assembly over long time-scales. Our simulations of clathrin-coat assembly in CME reveal how the formation of structured lattices impacts the kinetics of assembly, and how localization to the membrane can stabilize large, dynamic assemblies not observed in solution. We also recently developed a relatively simple equilibrium theory to quantify how localization of protein binding partners to the membrane can dramatically enhance binding through dimensionality reduction, providing a trigger for assembly. Tuning the speed and success of vesicle formation can be sensitively controlled by the stoichiometry of assembly components, particularly those that control membrane localization through lipid binding. Our results suggest that stoichiometric balance and membrane localization can act as a potent regulators of self-assembly, and our reaction-diffusion software provides a powerful tool to characterize mechanisms of regulation within the cell.

Banu Ozkan
Johns Hopkins University
Margaret E Johnson
Wednesday, April 10, 2019