An Ensemble-Based Protocol for the Computational Prediction of Helix-Helix Interactions in G Protein-Coupled Receptors using Coarse-Grained Molecular Dynamics.
An Ensemble-Based Protocol for the Computational Prediction of Helix-Helix Interactions in G Protein-Coupled Receptors using Coarse-Grained Molecular Dynamics.
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DOI：
10.1021/acs.jctc.6b01246
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发表时间：
2017-05-09
影响因子：
5.5
通讯作者：
Townsend-Nicholson A
中科院分区：
文献类型：
--
作者：
Altwaijry NA;Baron M;Wright DW;Coveney PV;Townsend-Nicholson A
准确识别 G 蛋白偶联受体 (GPCR) 寡聚体之间的特定相互作用点对于设计针对寡聚受体靶点的受体配体至关重要。粗粒度分子动力学计算机模拟方法将提供一种令人信服的方法来识别这些特定的蛋白质-蛋白质相互作用，并且可以应用于已知的感兴趣的寡聚体，也可以作为高通量筛选来识别新的寡聚靶标。然而，为了有效，这种计算机建模必须提供准确、精确和可重复的信息。最近，使用基于集合的全原子分子动力学方法在许多生物系统中实现了这一点。在本研究中，我们描述了基于集成的粗粒度模拟的等效方法。我们报告了该方法在应用于已知寡聚的四种不同 GPCR 时的性能，使用误差分析来确定整体大小和所需的单个副本模拟时间。我们对参与腺苷 A2A 受体第五跨膜结构域寡聚化的残基之间距离的测量与现有的生物物理数据非常一致，并提供了无法通过实验确定的接触界面性质的信息。据报道，在同型二聚体中形成接触点的视紫红质、CXCR4 和 β1AR 跨膜结构域之间的距离计算与从实验结构数据获得的相应测量值密切相关，从而提供了通过计算预测接触界面的能力。有趣的是，误差分析可以识别非相互作用区域。我们的结果证实，使用这种新颖的方法可以可靠地预测 GPCR 相互作用。
The accurate identification of the specific points of interaction between G protein-coupled receptor (GPCR) oligomers is essential for the design of receptor ligands targeting oligomeric receptor targets. A coarse-grained molecular dynamics computer simulation approach would provide a compelling means of identifying these specific protein–protein interactions and could be applied both for known oligomers of interest and as a high-throughput screen to identify novel oligomeric targets. However, to be effective, this in silico modeling must provide accurate, precise, and reproducible information. This has been achieved recently in numerous biological systems using an ensemble-based all-atom molecular dynamics approach. In this study, we describe an equivalent methodology for ensemble-based coarse-grained simulations. We report the performance of this method when applied to four different GPCRs known to oligomerize using error analysis to determine the ensemble size and individual replica simulation time required. Our measurements of distance between residues shown to be involved in oligomerization of the fifth transmembrane domain from the adenosine A2A receptor are in very good agreement with the existing biophysical data and provide information about the nature of the contact interface that cannot be determined experimentally. Calculations of distance between rhodopsin, CXCR4, and β1AR transmembrane domains reported to form contact points in homodimers correlate well with the corresponding measurements obtained from experimental structural data, providing an ability to predict contact interfaces computationally. Interestingly, error analysis enables identification of noninteracting regions. Our results confirm that GPCR interactions can be reliably predicted using this novel methodology.
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影响因子：
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