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在具有与序列无关的FG核孔蛋白的核孔复合体粗粒度模型中选择性和特异性的出现。

Emergence of selectivity and specificity in a coarse-grained model of the nuclear pore complex with sequence-agnostic FG-Nups.

作者信息

Patel Manoj K, Chakrabarti Buddhapriya, Panwar Ajay S

机构信息

Department of Metallurgical Engineering and Materials Science, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India.

Department of Physics, Sheffield University, UK.

出版信息

Phys Chem Chem Phys. 2023 Dec 13;25(48):32824-32836. doi: 10.1039/d3cp03746k.

Abstract

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.

摘要

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。

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