Selective transport of the nuclear pore complex studied through all-atom and coarse-grained molecular dynamics simulations
As the only pathways connecting the cell’s nucleus and cytoplasm, nuclear pore complexes (NPCs) enable and control the import and export between cell’s cytoplasm and nucleoplasm. The NPC allows small molecules (<40 KDa) to diffuse freely into and out of the nucleus, while excluding large molecules, which are only allowed to pass when bound to transport receptors. Anchored on the inner surface of the NPC central pore are many intrinsically unstructured FG-nups, proteins that contain phenylalanine-glycine repeating sequences (FG-repeats) separated by hydrophilic linker regions. Because of the unstructured nature of FG-nups, no imaging method has been able to capture the collective conformation of these proteins in detail. However, their collective behavior inside the NPC central pore is important to understand the NPC’s selective transport. In this thesis, molecular dynamics has been used to model and study a representative volume of the FG-nup-filled central pore. One FG-nup was divided into 25 segments, each containing 100 amino acids. The 25 segments were then tethered onto a planar surface to mimic the anchoring of FG-nups onto the central pore surface, forming a 5 × 5 array. Separation between tethering points was adjusted to render a similar FG-repeat density as that of the NPC. Computational simulations of the array suggested a dynamic brush-like structure, inside which the FG-nup segments form different bundles. Many FG-repeats were observed on the bundle surface without binding to another FG-repeat, offering a favorable environment for transport receptors, proteins that bind to FG-repeats as shown by both experiment and simulation. Further simulations confirmed that the brush-like structure is able to distinguish between transport receptors and inert proteins at its entrance. During the 200 ns simulations, transport receptor NTF2 gradually entered the brush while the inert protein barely did. Although both NTF2 and the inert protein were found to have many FG-repeats bound to them, binding events lasted only for short durations for the inert protein. The brush-like structure proposed and studied here shows great promise in functioning as the selective barrier of the NPC.
Nuclear pore complex, NPC selective transport, FG-nups, FG-repeats, Transport receptors, Molecular dynamics, MD simulations
University of Illinois - Urbana-Champaign
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University of Illinois at Urbana-Champaign