Coarse-Grained Molecular Dynamics of the Natively-Unfolded Domain of the NPC
Transport through the nuclear pore complex (NPC) is mediated through natively unfolded FG-Nups. In this study, we address several questions regarding the role of FG-Nups by means of a one-bead-per-amino acid (1 BPA) molecular dynamics model. We show that inside the NPC the FG-Nups collectively form a high-density, doughnut-like distribution, which is rich in FG repeats. This specific doughnut shape is encoded in the amino acid sequence of the FG-Nups. We compare our simulations with permeability experiments and find a strong correlation between passive transport through the NPC and the average density of the FG-Nups at the central core region of the pore. Furthermore, we use umbrella sampling to obtain the potential of mean force (PMF) distribution for model kap–cargo complexes along the central axis of the pore. We find that the energy barrier for passive transport is size dependent, with inert cargo molecules larger than 5 nm in diameter effectively being excluded from transport. PMF curves of the Kap–cargo complexes show that the presence of several hydrophobic binding spots on the surface of large cargo complexes can lower the energy barrier below kBT for an optimal spacing of 1.4 nm, which is close to reported experimental values. Finally, we capture our simulations in a simple transport model which describes the energy barrier of the NPC as a function of diameter and hydrophobicity of the Kap–cargo complex, highlighting the sensitive balance between cargo being trapped, expelled, and transported.
- Yamada J, Phillips J, Patel S, Goldfien G, Calestagne-Morelli A, Huang H, Reza R, Acheson J, Krishnan V, Newsam S et al (2010) A bimodal distribution of two distinct categories of intrinsically disordered structures with separate functions in FG nucleoporins. Mol Cell Proteomics 9:2205–2224CrossRefPubMedPubMedCentralGoogle Scholar