The material exchange between the nucleus and the cytoplasm is fundamental for eukaryotic cells. They maintain cellular functions by constantly transporting nucleic acids and proteins across the nuclear membrane. The transportation of macromolecules happens through nanopores on the nuclear membrane, called “nuclear pore complexes” (NPCs). NPCs distinguish transported macromolecules on the basis of their morphology and surface chemistry and open their gateways only to specific molecules. This selective nature of the NPC-mediated molecular transportation is essential for keeping the nuclear components intact and enforcing the functions of the nucleus, such as gene regulation, protein synthesis, and mechanotransduction. Despite the vital role of the NPC in cell and nuclear biology, the detailed mechanisms underlying how the NPC works are still largely unknown.

The critical components of NPCs creating the selective gateway are natively unfolded phenylalanine- and glycine-rich proteins called “FG-nucleoporins” (FG-Nups). FG-Nups are flexible polymers tethered to the inner wall of the NPC that form the brush-like structure inside the nuclear pore. FG-Nups dynamically change their collective conformations while molecules are transported through an NPC. Our working hypothesis was that the corresponding change in their conformational entropy determines the transportability of molecules, making the NPC work as a selective sieve. We investigated this hypothesis by computationally modeling the spatial statistics of FG-Nups inside the NPC and calculating their free energy, i.e., the balance between the conformational entropy and the energetic gain through molecular interactions.

The cover image for the September 7 issue of Biophysical Journal features the computationally calculated mean density distribution of FG-Nups inside an NPC while a spherical molecule is translocating through it. Viewed from the top of the nuclear pore, the mean density of FG-Nups forms the octagonally symmetrical distribution, which changes depending on the translocating molecule’s morphology and surface chemistry. We calculated the free energy associated with each FG-Nup distribution and showed that the change in free energy could explain the difference in molecular transportability through the NPC.

Our study proposed a physical mechanism for selective molecular transport through NPCs. This understanding can be potentially applied to designing nuclear-targeted drugs that efficiently overcome the NPC barrier or to developing nano-filtering devices inspired by NPCs.

- Atsushi Matsuda and Mohammad R. K. Mofrad