The membrane complex between transducin and dark-state rhodopsin exhibits large-amplitude interface dynamics on the sub-microsecond timescale: insights from all-atom MD simulations.
The membrane complex between transducin and dark-state rhodopsin exhibits large-amplitude interface dynamics on the sub-microsecond timescale: insights from all-atom MD simulations.
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转导蛋白和暗态视紫红质之间的膜复合物在亚微秒时间尺度上表现出大幅界面动力学：来自全原子 MD 模拟的见解。
DOI：
10.1016/j.jmb.2010.02.032
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发表时间：
2010
影响因子：
5.6
通讯作者：
Garcia,AngelE
中科院分区：
文献类型：
--
作者：
Sgourakis,NikolaosG;Garcia,AngelE
视紫红质是一类G蛋白偶联受体的原型，是所有七跨膜结构域蛋白的一个非常重要的模型系统。视紫红质和transducin，其细胞内的G-蛋白对应物之间的相互作用，以及由于热运动在这些相互作用的波动的表征是需要了解早期事件的信号转导机制。在这项研究中，我们使用全原子分子动力学模拟的视紫红质和异源三聚体转导蛋白（Gαβγ）之间的跨膜蛋白复合物在全原子DOPC（1，2-dioleoylsn-glycero-3-phosphocholine）膜-水环境。基于微秒级模拟轨迹的分析，我们描述了系统的动力学及其对蛋白质亚基结构特征的影响。我们的模拟描述了一个高度动态的相互作用界面，其中系统在10- 100-ns的时间尺度上在不同的结构域方向之间交替，可以进一步分类为涉及蛋白质亚基上不同结构特征之间接触的相互作用模式。我们将我们的结果与来自各种研究的实验测量和活化视紫红质的高分辨率模型相关联。监测参与激活过程的关键结构特征，沿着我们的模拟轨迹表明存在广泛的动态在黑暗适应状态，包括运动的Y223从螺旋3朝向“离子锁”相互作用的保守ERY基序。这里所示的动态图片是一致的框架中，暗态波动样品的构象与激活状态一致。这些结果提供了一个原子级的完整的复合物的动力学描述，并进一步建议新的诱变实验，可用于研究该模型膜蛋白受体系统的稳定性和动力学。
Rhodopsin, the prototype class A G-protein-coupled receptor, is a very important model system for all seven-transmembrane domain proteins. Characterization of the interactions between rhodopsin and transducin, its intracellular G-protein counterpart, and the fluctuations in these interactions due to thermal motions is required for an understanding of early events in the mechanism of signal transduction. In this study, we used all-atom molecular dynamics simulations of a transmembrane protein complex between rhodopsin and the heterotrimeric transducin (Gαβγ) in an all-atom DOPC (1,2-dioleoylsn-glycero-3-phosphocholine) membrane–water environment. Based on the analysis of a microsecond-timescale simulation trajectory, we characterized the dynamics of the system and its effects in the structural features of the protein subunits. Our simulations describe a highly dynamic interaction interface where the system is alternating between distinct domain orientations at the 10- to 100-ns timescale that can be further classified into interaction modes involving contacts between distinct structural features on the protein subunits. We related our results with experimental measurements from a variety of studies and high-resolution models of activated rhodopsin. Monitoring key structural features that are involved in the activation process along our simulation trajectory indicates the presence of extensive dynamics in the dark-adapted state, including a motion of Y223 from helix 3 toward the “ionic-lock” interactions of the conserved ERY motif. The dynamic picture shown here is consistent with a framework in which the dark-state fluctuations sample conformations consistent with the activated state. These results provide an atomic-level description of the dynamics of the full complex and further suggest novel mutagenesis experiments that can be used to investigate the stability and dynamics of this model membrane protein receptor system.