Molecular insights into the binding variance of the SARS-CoV-2 spike with human, cat and dog ACE2 proteins
Molecular insights into the binding variance of the SARS-CoV-2 spike with human, cat and dog ACE2 proteins
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对 SARS-CoV-2 刺突与人、猫和狗 ACE2 蛋白结合差异的分子洞察
DOI：
10.1039/d1cp01611c
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发表时间：
2021
影响因子：
3.3
通讯作者：
Zhang Shengli
中科院分区：
文献类型：
--
作者：
Zang Yongjian;Li Xuhua;Zhao Yizhen;Wang He;Hao Dongxiao;Zhang Lei;Yang Zhiwei;Yuan Xiaohui;Zhang Shengli
SARS-CoV-2最近在人类中引起流行，对全球公共卫生构成巨大威胁。血管紧张素转换酶2（ACE 2）作为SARS冠状病毒2的主要受体，存在于与人类密切接触的不同宿主体内，尤其是猫和狗。然而，SARS-CoV-2的刺突受体结合结构域（RBD）如何与人ACE 2（hACE 2）、猫ACE 2（cACE 2）和狗ACE 2（dACE 2）合作以及结合的变化的潜在机制仍然在很大程度上未被解决。因此，我们通过全原子分子动力学模拟探索了尖峰RBD与cACE 2、dACE 2和hACE 2的结合行为。根据结合自由能和残基相互作用，尖峰RBD与cACE 2、dACE 2和hACE 2具有各自的结合特异性，并且结合亲和力按hACE 2、cACE 2、dACE 2的顺序降低，主要是由于cACE 2或dACE 2中氨基酸Q24 L、H34 Y和M82 T的变化。此外，丙氨酸扫描分析结果验证了RBD的一些关键残基与ACE 2的相互作用，并提供了可能影响SARS-CoV-2传播性或免疫应答的氨基酸变异的线索。在所有hACE 2-RBD、cACE 2-RBD和dACE 2-RBD系统中发现ACE 2与RBD的动态相关强度降低。ACE 2蛋白在锌金属肽酶结构域中表现出可变的运动模式，这诱导了ACE 2和RBD之间的不同相互作用。我们的研究表明，锌金属肽酶结构域的运动模式是至关重要的RBD与ACE 2的结合行为。这些发现有助于我们理解SARS-CoV-2刺突与各种ACE 2的选择性识别，并进一步阐明结合机制。
SARS-CoV-2 has recently caused an epidemic in humans and poses a huge threat to global public health. As a primary receptor of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) exists in different hosts that are in close contact with humans, especially cats and dogs. However, the underlying mechanism of how the spike receptor binding domain (RBD) of SARS-CoV-2 cooperates with human ACE2 (hACE2), cat ACE2 (cACE2) and dog ACE2 (dACE2) and the variation in binding remains largely unsolved. Therefore, we explored the binding behavior of the spike RBD with cACE2, dACE2 and hACE2 via all-atom molecular dynamics simulations. In accordance with the binding free energies and residue interactions, the spike RBD has respective binding specificities with cACE2, dACE2 and hACE2, and the binding affinities decrease in the order of hACE2, cACE2, dACE2, mainly due to changes in the amino acids Q24L, H34Y, and M82T in cACE2 or dACE2. Furthermore, alanine scanning analysis results validated some key residues of the spike RBD interact with ACE2 and provided clues to the variation of amino acid that could influence the transmissibility or immune responses of SARS-CoV-2. Decreasing dynamic correlations strengths of ACE2 with the RBD were found in all hACE2–RBD, cACE2–RBD and dACE2–RBD systems. The ACE2 protein shows variable motion modes across the zinc metallopeptidase domain, which induces different interactions between ACE2 and the RBD. Our studies reveal that the motion pattern of the zinc metallopeptidase domain is critical to the binding behavior of RBD with ACE2. These findings could aid our understanding of selective recognition involving various ACE2 with the SARS-CoV-2 spike and shed further light on the binding mechanisms.