Probing the origin of tubulin rigidity with molecular simulations
Probing the origin of tubulin rigidity with molecular simulations
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DOI：
10.1073/pnas.0806113105
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发表时间：
2008-10-14
影响因子：
11.1
通讯作者：
Joshi, Harshad
中科院分区：
文献类型：
--
作者：
Dima, Ruxandra I.;Joshi, Harshad
微管蛋白异二聚体是微管的组成部分，微管是细胞骨架的主要组成部分，其机械特性是细胞生命的基础。我们通过探测微管蛋白单体和微管蛋白异二聚体的能量景观特征，揭示了微管中机械响应的微观起源。为了阐明解折叠途径的结构并揭示多种解折叠路径，我们对微管蛋白的自组织聚合物（SOP）模型进行了模拟。 SOP 表示是对链的粗粒度描述，它使我们能够以与单分子实验中使用的非常匹配的加载速率和时间尺度进行力诱导模拟。我们表明，每个单体的强制展开涉及到拉伸状态路径的分叉。 C 端结构域展开后，根据单体和途径，从 N 端结构域或中间结构域继续展开。与单体的解折叠复杂性相反，二聚体仅根据一种对应于β-微管蛋白的C端结构域和部分中间结构域的解开的途径展开。我们发现这种令人惊讶的行为是由于单体之间界面的粘弹性特性造成的。我们通过调查各种亚稳态中间体的结构，绘制了微管蛋白复杂能量图谱的精确特征，在二聚体情况下，这些中间体的特征仅在于β-微管蛋白单体的变化。
Tubulin heterodimers are the building blocks of microtubules, a major component of the cytoskeleton, whose mechanical properties are fundamental for the life of the cell. We uncover the microscopic origins of the mechanical response in microtubules by probing features of the energy landscape of the tubulin monomers and tubulin heterodimer. To elucidate the structures of the unfolding pathways and reveal the multiple unfolding routes, we performed simulations of a self-organized polymer (SOP) model of tubulin. The SOP representation, which is a coarse-grained description of chains, allows us to perform force-induced simulations at loading rates and time scales that closely match those used in single-molecule experiments. We show that the forced unfolding of each monomer involves a bifurcation in the pathways to the stretched state. After the unfolding of the C-term domain, the unraveling continues either from the N-term domain or from the middle domain, depending on the monomer and the pathway. In contrast to the unfolding complexity of the monomers, the dimer unfolds according to only one route corresponding to the unraveling of the C-term domain and part of the middle domain of beta-tubulin. We find that this surprising behavior is due to the viscoelastic properties of the interface between the monomers. We map precise features of the complex energy landscape of tubulin by surveying the structures of the various metastable intermediates, which, in the dimer case, are characterized only by changes in the beta-tubulin monomer.