FG-Nup sequence length polydispersity enhances selectivity of nuclear pore complex translocation

The central channel of the nuclear pore complex (NPC) exhibits polydispersity in the FG-nucleoporin (FG-Nup) sequence length, with longer FG-Nups on the periphery and shorter FG-Nups in the interior of the pore. A minimal, coarse-grained model and Langevin dynamics simulations were used to investigate the functional role of FG-Nup polydispersity in NPC transport. The NPC was modelled as a cylindrical pore lined with a random copolymer brush composed of hydrophobic and hydrophilic segments, mimicking FG-Nups. Two model NPCs were considered to simulate the translocation of a karyopherin-bound spherical cargo (12 nm spherical tracers): 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 the 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. This 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.