How calcium ion binding induces the conformational transition of the calmodulin N-terminal domain-an atomic level characterization
How calcium ion binding induces the conformational transition of the calmodulin N-terminal domain-an atomic level characterization
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钙离子结合如何诱导钙调蛋白 N 末端结构域的构象转变 - 原子水平表征
DOI：
10.1039/c9cp03917a
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发表时间：
2019-09-28
影响因子：
3.3
通讯作者：
Zhang，Zhuqing
中科院分区：
文献类型：
--
作者：
Zhao，Likun;Lai，Luhua;Zhang，Zhuqing
变构在许多生物过程的调节中发挥着重要作用，例如信号转导和转录调节。尽管通过实验和理论研究在理解变构机制方面取得了巨大进展，但变构过程的细节仍然不清楚。在这里，我们使用钙调蛋白 (nCaM) 的 N 末端结构域作为模型蛋白，通过广泛且无偏差的分子动力学模拟，报道了 Ca2+ 结合诱导的变构过程的原子水平表征。在两条轨迹中，发现Ca2+首先与EF-hand 2结合，然后在第二次Ca2+与EF-hand 1完全结合的协助下诱导nCaM从Apo构象转变为Holo状态。结合顺序与最近的实验结果一致。模拟还表明，两个 EF-hand 协同改变构象，并且 EF-hand 2 显示出更早且更渐进的构象转变。同时，Ca2+结合触发的nCaM变构过程可能以类似两种状态的方式在数百纳秒内完成。这通过有偏差的模拟得到了验证，其中 Ca2+ 离子被限制在结合位点附近。这项工作提供了由 Ca2+ 结合触发的 nCaM 构象转变的分子细节。
Allostery plays important roles in the regulation of many biological processes, such as signal transduction and transcriptional regulation. Although great advances have been achieved in understanding the allosteric mechanism through experimental and theoretical investigations, the details of the allosteric process are still not clear. Here, using the N-terminal domain of calmodulin (nCaM) as the model protein, we reported the atomic level characterization of the allosteric process induced by Ca2+ binding through extensive and unbiased molecular dynamics simulations. In two trajectories, it was found that Ca2+ first binds to EF-hand 2 and then induces the conformational transformation of nCaM from the Apo to Holo state assisted by second Ca2+ binding to EF-hand 1 completely. The binding order was consistent with a recent experimental result. The simulations also indicated that the two EF-hands changed conformations synergistically and the EF-hand 2 showed an earlier and more gradual conformational transition. Meanwhile, the allosteric process of nCaM triggered by Ca2+ binding might be completed within hundreds of nanoseconds in a two-state-like manner. This was validated by biased simulations, in which the Ca2+ ions were restrained near the binding sites. This work provides the molecular details of the conformational transition of nCaM triggered by Ca2+ binding.