Spatial dimension and binding kinetics between FG-repeats characterize the free/bound diffusion of molecules inside the nuclear pore complex.

Abstract

The nuclear pore complex (NPC) is an exclusive gateway connecting the cytoplasm and the nucleus. The NPC works as a selective barrier allowing the free diffusion of small (less than 5-9 nanometer in diameter) molecules and the facilitated transport of small-to-large karyopherin-associated molecules. The selective transport is regulated by FG-Nups, intrinsically disordered proteins filling the transport channel of the NPC. FG-Nups contain many phenylalanine- and glycine-rich motifs, which interact with each other as well as with the hydrophobic pockets on karyopherins. The ability of FG-Nups to selectively transport molecules is the exquisite feature that the cell has developed, and understanding its mechanism would potentially boost their utilization for future engineering applications. In this study, we aimed to identify the detailed characteristics regarding the diffusion of molecules transported through the FG-Nups barrier. We developed a Brownian dynamics model, which represents the FG-Nups as coarse-grained bead-springs tethered to the inner wall of the cylindrical channel and simulates their motion by the overdamped Langevin equation. We placed spherical cargo in the simulation system and studied their diffusion characteristics while changing the cargo size and the binding kinetics rate between FG-motifs. The simulation result suggested that the cargo switches between two diffusive modes, free diffusion and bound diffusion, depending on its association with FG-Nups. The selectivity emerged due to the limited availability of free diffusion for oversized cargos. Besides, it showed that a specific range of the binding rate is allowed to produce a reasonably large amount of the diffusion constant for bound diffusion.