FG-Nup Sequence Length Polydispersity Enhances Selectivity of NPC Translocation

The central channel of the nuclear pore complex (NPC) exhibits polydispersity in FG-nucleoporin (FG-Nup) sequence length, with longer FG-Nups on the periphery and shorter FG-Nups in the interior of the pore. The functional role of FG-Nup polydispersity in NPC transport was investigated using a minimal, coarse-grained model and Langevin dynamics simulations. The NPC was modelled as a cylindrical pore lined with a random copolymer brush composed of hydrophobic and hydrophilic segments, mimicking FG-Nups. The total number of hydrophobic segments corresponded to the fraction of FG-repeats, f, in the FG-Nups. The translocation of karyopherin-bound spherical cargo (12 nm spherical tracers) was simulated through two model NPCs; a homogeneous NPC (h-NPC) with uniform FG-Nup lengths and an inhomogeneous NPC (ih-NPC) featuring shorter FG-Nups in the middle and longer FG-Nups at the periphery. The ih-NPC demonstrated enhanced selectivity and significantly higher passage probabilities for karyopherin-bound tracers, with an increase of up to 90% compared to h-NPC. Analysis of binding contacts between tracers and FG-Nup hydrophobic segments revealed that tracer translocation was facilitated by a handover process between successive FG-Nups along the NPC length. The enhanced selectivity of the ih-NPC was attributed to an increase in binding contacts of the tracer with the shorter FG-Nups in its middle region. These findings provide a biophysical basis for the evolutionary significance of FG-Nup polydispersity in selective NPC transport.