Brownian Dynamics Simulation of Nucleocytoplasmic Transport: A Coarse-Grained Model for the Functional State of the Nuclear Pore Complex

The nuclear pore complex (NPC) regulates molecular traffic across the nuclear envelope (NE). Selective transport happens on the order of milliseconds and the length scale of tens of nanometers; however, the transport mechanism remains elusive. Central to the transport process is the hydrophobic interactions between karyopherins (kaps) and Phe-Gly (FG) repeat domains. Taking into account the polymeric nature of FG-repeats grafted on the elastic structure of the NPC, and the kap-FG hydrophobic affinity, we have established a coarse-grained model of the NPC structure that mimics nucleocytoplasmic transport. To establish a foundation for future works, the methodology and biophysical rationale behind the model is explained in details. The model predicts that the first-passage time of a 15 nm cargo-complex is about 2.6±0.13 ms with an inverse Gaussian distribution for statistically adequate number of independent Brownian dynamics simulations. Moreover, the cargo-complex is primarily attached to the channel wall where it interacts with the FG-layer as it passes through the central channel. The kap-FG hydrophobic interaction is highly dynamic and fast, which ensures an efficient translocation through the NPC. Further, almost all eight hydrophobic binding spots on kap-β are occupied simultaneously during transport. Finally, as opposed to intact NPCs, cytoplasmic filaments-deficient NPCs show a high degree of permeability to inert cargos, implying the defining role of cytoplasmic filaments in the selectivity barrier. Author Summary: Perforating and spanning the nuclear envelope (NE), the nuclear pore complex (NPC) is a supramolecular assembly that regulates all traffic between the nucleus and cytoplasm. As the unique gateway to the nucleus, NPC selectively facilitates the transport of large cargo while offering a relatively unobstructed pathway for small molecules and ions. Despite the high throughput of about 1000 translocations per NPC per second, the NPC strictly controls the passage of individual cargos. However, the dynamic mechanism of nucleocytoplasmic transport is poorly understood. It is too difficult to experiment on the transport mechanism within the confined geometry of this tiny pore in vivo. Currently, only computational techniques can elucidate the detailed events happening at this tiny pore with a refined spatiotemporal resolution to account for transient bonds. Based on experimental data regarding the NPC structure and nucleocytoplasmic transport, we have established a coarse-grained model of the functional state of the NPC. The model mimics nucleocytoplasmic transport and allows us to directly observe the processes happening within the pore from a biophysical perspective. The first-passage time of a single cargo-complex is found to be about 2.6 ms. Furthermore, kap-FG hydrophobic bonds are highly dynamic and short-lived, ensuring efficient transport.