Dynein is a cytoskeletal molecular motor protein that moves along the microtubule (MT) and transports various cellular cargos during its movement. Using standard Molecular Dynamics (MD) simulation, Principle Component Analysis (PCA), and Normal Mode Analysis (NMA) methods, this investigation studied large-scale movements and local interactions of dynein’s Microtubule Binding Domain (MTBD) when bound to tubulin heterodimer subunits. Examination of the interactions between the MTBD segments, and their adjustments in terms of intra- and intermolecular distances at the interfacial area with tubulin heterodimer, particularly at α-H16, β-H18, and β-tubulin C-terminal tail (CTT), was the main focus of this study. The specific intramolecular interactions, electrostatic forces, and the salt bridge residue pairs were shown to be the dominating factors in orchestrating movements of the MTBD and MT interfacial segments in the dynein’s low-high-affinity binding modes. Important interactions included β-Glu447 and β-Glu449 (CTT) with Arg3469 (MTBD-H6), Lys3472 (MTBD-H6-H7 loop) and Lys3479 (MTBD-H7); β-Glu449 with Lys3384 (MTBD-H8), Lys3386 and His3387 (MTBD-H1). The structural and precise position, orientation, and functional effects of the CTTs on the MT-MTBD, within reasonable cut-off distance for non-bonding interactions and under physiological conditions, are unavailable from previous studies. The absence of the residues in the highly flexible MT-CTTs in the experimentally solved structures is perhaps in some cases due to insufficient data from density maps, but these segments are crucial in protein binding. The presented work contributes to the information useful for the MT-MTBD structure refinement.

中文翻译：

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β-微管蛋白的 C 末端尾部及其在动力蛋白结合模式改变中的作用。


动力蛋白是一种细胞骨架分子运动蛋白，沿着微管 (MT) 移动，并在其移动过程中运输各种细胞货物。本研究使用标准分子动力学 (MD) 模拟、主成分分析 (PCA) 和正态模式分析 (NMA) 方法，研究了动力蛋白微管结合域 (MTBD) 与微管蛋白异二聚体亚基结合时的大规模运动和局部相互作用。检查 MTBD 片段之间的相互作用，以及它们与微管蛋白异二聚体界面区域的分子内和分子间距离的调整，特别是在 α-H16、β-H18 和 β-微管蛋白 C 末端尾部 (CTT)，是本研究的主要焦点。特定的分子内相互作用、静电力和盐桥残基对被证明是在动力蛋白的低-高亲和力结合模式下协调 MTBD 和 MT 界面片段运动的主导因素。重要的相互作用包括 β-Glu447 和 β-Glu449 (CTT) 与 Arg3469 (MTBD-H6)、Lys3472 (MTBD-H6-H7 环) 和 Lys3479 (MTBD-H7)； β-Glu449 与 Lys3384 (MTBD-H8)、Lys3386 和 His3387 (MTBD-H1)。在非键合相互作用的合理截止距离内以及在生理条件下，CTT 对 MT-MTBD 的结构和精确位置、方向和功能影响是以前的研究无法获得的。在某些情况下，实验解决的结构中高度灵活的 MT-CTT 中残基的缺失可能是由于密度图数据不足，但这些片段在蛋白质结合中至关重要。所提出的工作为 MT-MTBD 结构细化提供了有用的信息。