Accurate Binding Configuration Prediction of a G-Protein-Coupled Receptor to Its Antagonist Using Multicanonical Molecular Dynamics-Based Dynamic Docking
Accurate Binding Configuration Prediction of a G-Protein-Coupled Receptor to Its Antagonist Using Multicanonical Molecular Dynamics-Based Dynamic Docking
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DOI：
10.1021/acs.jcim.1c00712
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发表时间：
2021-09-22
影响因子：
5.6
通讯作者：
Kamiya, Narutoshi
中科院分区：
文献类型：
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作者：
Bekker, Gert-Jan;Araki, Mitsugu;Kamiya, Narutoshi
我们在原型g蛋白偶联受体（GPCR）系统（β(2)-肾上腺素能受体）及其拮抗剂阿普萘洛尔（alprenolol）之间进行了动态对接，使用了一种增强的构象采样方法，即多电子分子动力学（McMD），该方法不依赖于任何先前的知识来定义反应坐标。尽管我们之前已经将基于mcmd的动态对接协议应用于各种球状蛋白系统，但由于其复杂的设计（包括脂质双分子层）以及难以采样存在于GPCR深处的结合位点的构型空间，因此将其应用于GPCR系统将是困难的。我们的模拟采样了广泛的配体结合和配体非结合结构，我们在48亩的生产运行中测量了427个结合事件。对系综的分析揭示了几个稳定和亚稳定的结构，其中在全局自由能最小值处最稳定的结构与实验结构相匹配。另外，我们用典型的分子动力学模拟来改进和验证这些结构，揭示了大多数中间产物足够稳定，可以将配体困在这些中间状态，进一步验证了我们的预测结果。考虑到到达正构结合位点的困难，对化合物进行化学优化，使其在靠近口袋入口的位置结合，可能会产生高亲和力的变构抑制剂。因此，我们表明，我们的方法的应用可以用来为靶向gpcr的药物的合理设计提供重要的见解。
We have performed dynamic docking between a prototypic G-protein-coupled receptor (GPCR) system, the beta(2)-adrenergic receptor, and its antagonist, alprenolol, using one of the enhanced conformation sampling methods, multicanonical molecular dynamics (McMD), which does not rely on any prior knowledge for the definition of the reaction coordinate. Although we have previously applied our McMD-based dynamic docking protocol to various globular protein systems, its application to GPCR systems would be difficult because of their complicated design, which include a lipid bilayer, and because of the difficulty in sampling the configurational space of a binding site that exists deep inside the GPCR. Our simulations sampled a wide array of ligand-bound and ligand-unbound structures, and we measured 427 binding events during our 48 mu s production run. Analysis of the ensemble revealed several stable and meta-stable structures, where the most stable structure at the global free energy minimum matches the experimental one. Additional canonical MD simulations were used for refinement and validation of the structures, revealing that most of the intermediates are sufficiently stable to trap the ligand in these intermediary states and furthermore validated our prediction results. Given the difficulty in reaching the orthosteric binding site, chemical optimization of the compound for the second ranking configuration, which binds near the pocket's entrance, might lead to a high-affinity allosteric inhibitor. Accordingly, we show that the application of our methodology can be used to provide crucial insights for the rational design of drugs that target GPCRs.