Patel Manoj K, Chakrabarti Buddhapriya, Panwar Ajay S
Department of Metallurgical Engineering and Materials Science, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India.
Department of Physics, Sheffield University, UK.
Phys Chem Chem Phys. 2023 Dec 13;25(48):32824-32836. doi: 10.1039/d3cp03746k.
The role of hydrophobicity of phenylalanine-glycine nucleoporins (FG-Nups) in determining the transport of receptor-bound cargo across the nuclear pore complex (NPC) is investigated using Langevin dynamics simulations. A coarse-grained, minimal model of the NPC, comprising a cylindrical pore and hydrophobic-hydrophilic random copolymers for FG-Nups was employed. Karyopherin-bound receptor-cargo complexes (Kaps) were modeled as rigid, coarse-grained spheres without (inert) and with (patchy) FG-binding hydrophobic domains. With a sequence-agnostic description of FG-Nups and the absence of any anisotropies associated with either NPC or cargo, the model described tracer transport only as a function of FG-Nup hydrophobicity, . The simulations showed the emergence of two important features of cargo transport, namely, NPC selectivity and specificity. NPC selectivity to patchy tracers emerged due to hydrophobic Kap-FG interactions and despite the sequence-agnostic description of FG-Nups. Furthermore, NPC selectivity was observed only in a specific range of FG-hydrophobic fraction, 0.05 ≤ ≤ 0.20, resulting in specificity of NPC transport with respect to . Significantly, this range corresponded to the number fraction of FG-repeats observed in both and NPCs. This established the central role of the FG-hydrophobic fraction in determining NPC transport, and provided a biophysical basis for conservation of the FG-Nup hydrophobic fraction across evolutionarily distant NPCs. Specificity in NPC transport emerged from the formation of a hydrogel-like network inside the pore with a characteristic mesh size dependent on . This network rejected cargo for > 0.2 based on size exclusion, which resulted in enhanced translocation probability for 0.05 ≤ ≤ 0.20. Extended brush configurations outside the pore resulted in entropic repulsion and exclusion of inert cargo in this range. Thus, our minimal NPC model exhibited a hybrid cargo translocation mechanism, with aspects of both virtual gate and selective-phase models, in this range of FG-hydrophobic fraction.
利用朗之万动力学模拟研究了苯丙氨酸 - 甘氨酸核孔蛋白(FG - Nups)的疏水性在决定受体结合货物跨核孔复合体(NPC)运输中的作用。采用了一种粗粒度的NPC最小模型,该模型包括一个圆柱形孔和用于FG - Nups的疏水 - 亲水无规共聚物。与核转运蛋白结合的受体 - 货物复合物(Kaps)被建模为刚性的、粗粒度的球体,分别有无(惰性)和有(斑块状)FG结合疏水结构域。由于对FG - Nups采用了与序列无关的描述,且不存在与NPC或货物相关的任何各向异性,该模型仅将示踪剂运输描述为FG - Nup疏水性的函数。模拟结果显示了货物运输的两个重要特征,即NPC选择性和特异性。尽管对FG - Nups采用了与序列无关的描述,但由于疏水的Kap - FG相互作用,出现了NPC对斑块状示踪剂的选择性。此外,仅在特定的FG - 疏水分数范围内(0.05≤≤0.20)观察到NPC选择性,从而导致NPC运输相对于的特异性。值得注意的是,该范围对应于在酵母和脊椎动物NPC中观察到的FG重复序列的数量分数。这确立了FG - 疏水分数在决定NPC运输中的核心作用,并为跨进化距离较远的NPC保守FG - Nup疏水分数提供了生物物理基础。NPC运输的特异性源于孔内形成的类似水凝胶的网络,其特征网格尺寸取决于。基于尺寸排阻,该网络排斥> 0.2的货物,这导致0.05≤≤0.20时转运概率增加。孔外的扩展刷状构型导致熵排斥并在此范围内排除惰性货物。因此,在该FG - 疏水分数范围内,我们的最小NPC模型表现出一种混合货物转运机制,兼具虚拟门控和选择性相模型的特点。