Probing the flexibility of tropomyosin and its binding to filamentous actin using molecular dynamics simulations.
Probing the flexibility of tropomyosin and its binding to filamentous actin using molecular dynamics simulations.
复制标题
使用分子动力学模拟探讨原肌球蛋白的灵活性及其与丝状肌动蛋白的结合。
DOI：
10.1016/j.bpj.2013.09.003
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发表时间：
2013
影响因子：
3.4
通讯作者：
Hitchcock-DeGregori,SarahE
中科院分区：
文献类型：
--
作者：
Zheng,Wenjun;Barua,Bipasha;Hitchcock-DeGregori,SarahE
原肌球蛋白（Tm）是一种螺旋状蛋白，与丝状肌动蛋白（F-actin）结合，并通过在F-actin上的三个位置（阻断、关闭和开放位置）之间移动来调节其与肌动蛋白结合蛋白（如肌动蛋白）的相互作用。为了阐明Tm与f -肌动蛋白结合时柔韧性的分子细节，我们对Tm单独和Tm- f -肌动蛋白复合物在显式溶剂存在下进行了广泛的分子动力学模拟（总模拟时间约400 ns）。在仿真的基础上，系统地分析了多参数Tm线圈的局部柔性。我们发现在Tm中具有高局部柔韧性的区域和一些不稳定区域之间存在良好的相关性，包括六个核心丙氨酸簇。尽管f -肌动蛋白结合起到了稳定作用，但无论f -肌动蛋白是否存在，Tm的局部柔韧性分布基本不变。我们的模拟显示了从关闭位置到打开位置的各个Tm周期的可变波动。此外，我们基于模拟轨迹进行了Tm- f -actin结合计算，这支持了Tm灵活性对Tm- f -actin结合的重要性。我们确定了Tm与f -肌动蛋白动态相互作用的关键残基，其中许多残基在最近的突变研究中被发现具有重要的功能，其余的残基将成为未来突变实验的有希望的目标。
Tropomyosin (Tm) is a coiled-coil protein that binds to filamentous actin (F-actin) and regulates its interactions with actin-binding proteins like myosin by moving between three positions on F-actin (the blocked, closed, and open positions). To elucidate the molecular details of Tm flexibility in relation to its binding to F-actin, we conducted extensive molecular dynamics simulations for both Tm alone and Tm-F-actin complex in the presence of explicit solvent (total simulation time >400 ns). Based on the simulations, we systematically analyzed the local flexibility of the Tm coiled coil using multiple parameters. We found a good correlation between the regions with high local flexibility and a number of destabilizing regions in Tm, including six clusters of core alanines. Despite the stabilization by F-actin binding, the distribution of local flexibility in Tm is largely unchanged in the absence and presence of F-actin. Our simulations showed variable fluctuations of individual Tm periods from the closed position toward the open position. In addition, we performed Tm-F-actin binding calculations based on the simulation trajectories, which support the importance of Tm flexibility to Tm-F-actin binding. We identified key residues of Tm involved in its dynamic interactions with F-actin, many of which have been found in recent mutational studies to be functionally important, and the rest of which will make promising targets for future mutational experiments.