Molecular basis for higher affinity of SARS-CoV-2 spike RBD for human ACE2 receptor
Molecular basis for higher affinity of SARS-CoV-2 spike RBD for human ACE2 receptor
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DOI：
10.1002/prot.26086
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发表时间：
2021-04-26
影响因子：
2.9
通讯作者：
Varma, Sameer
中科院分区：
文献类型：
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作者：
Delgado, Julian M.;Duro, Nalvi;Varma, Sameer
与2002-2003年的SARS-CoV相比，严重急性呼吸综合征冠状病毒-2(SARS-CoV-2)造成的感染、死亡和经济中断要多得多。理解SARS-CoV-2 S高感染性的关键部分在于其宿主受体识别机制。实验表明，人血管紧张素转换酶2蛋白作为两种冠状病毒的主要受体，与冠状病毒S刺突蛋白的受体结合域结合得比SARS冠状病毒的刺突结合域更强。然而，这种结合亲和力差异的分子基础仍然无法从X射线结构中解释。为了超越从X射线结构中获得的洞察力，并研究热涨落在结构中的作用，我们使用了全原子分子动力学模拟。微秒长的模拟表明，虽然CoV和CoV-2 Spike-ACE2界面具有相似的构象结合模式，但CoV-2 Spike通过更大的极性接触组合与ACE2相互作用，平均使极性接触增加45%。相关分析和热力学计算表明，极性接触密度和动力学的差异源于界面残基空间排列的差异，以及界面残基和非界面残基之间的动力学耦合。这些结果表明，正在进行的设计SPEKE-ACE2多肽阻滞剂的努力将受益于纳入动力学信息以及变构耦合效应。
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused substantially more infections, deaths, and economic disruptions than the 2002-2003 SARS-CoV. The key to understanding SARS-CoV-2's higher infectivity lies partly in its host receptor recognition mechanism. Experiments show that the human angiotensin converting enzyme 2 (ACE2) protein, which serves as the primary receptor for both CoVs, binds to the receptor binding domain (RBD) of CoV-2's spike protein stronger than SARS-CoV's spike RBD. The molecular basis for this difference in binding affinity, however, remains unexplained from X-ray structures. To go beyond insights gained from X-ray structures and investigate the role of thermal fluctuations in structure, we employ all-atom molecular dynamics simulations. Microseconds-long simulations reveal that while CoV and CoV-2 spike-ACE2 interfaces have similar conformational binding modes, CoV-2 spike interacts with ACE2 via a larger combinatorics of polar contacts, and on average, makes 45% more polar contacts. Correlation analysis and thermodynamic calculations indicate that these differences in the density and dynamics of polar contacts arise from differences in spatial arrangements of interfacial residues, and dynamical coupling between interfacial and non-interfacial residues. These results recommend that ongoing efforts to design spike-ACE2 peptide blockers will benefit from incorporating dynamical information as well as allosteric coupling effects.