Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China; Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
Comput Biol Chem. 2022 Feb;96:107613. doi: 10.1016/j.compbiolchem.2021.107613. Epub 2021 Dec 1.
Coronavirus Disease 2019 (COVID-19) is an ongoing global health emergency that has caused tremendous stress and loss of life worldwide. The viral spike glycoprotein is a critical molecule mediating transmission of SARS-CoV-2 by interacting with human ACE2. However, through the course of the pandemics, there has not been a thorough analysis of the spike protein mutations, and on how these mutants influence the transmission of SARS-CoV-2. Besides, cases of SARS-CoV-2 infection among pets and wild animals have been reported, so the susceptibility of these animals requires great attention to investigate, as they may also link to the renewed question of a possible intermediate host for SARS-CoV-2 before it was transmitted to humans. With over 226,000 SARS-CoV-2 sequences obtained, we found 1573 missense mutations in the spike gene, and 226 of them were within the receptor-binding domain (RBD) region that directly interacts with human ACE2. Modeling the interactions between SARS-CoV-2 spike mutants and ACE2 molecules showed that most of the 74 missense mutations in the RBD region of the interaction interface had little impact on spike binding to ACE2, whereas several within the spike RBD increased the binding affinity toward human ACE2 thus making the virus likely more contagious. On the other hand, modeling the interactions between animal ACE2 molecules and SARS-CoV-2 spike revealed that many pets and wild animals' ACE2 had a variable binding ability. Particularly, ACE2 of bamboo rat had stronger binding to SARS-CoV-2 spike protein, whereas that of mole, vole, Mus pahari, palm civet, and pangolin had a weaker binding compared to human ACE2. Our results provide structural insights into the impact on interactions of the SARS-CoV-2 spike mutants to human ACE2, and shed light on SARS-CoV-2 transmission in pets and wild animals, and possible clues to the intermediate host(s) for SARS-CoV-2.
新型冠状病毒病（COVID-19）是一场持续的全球卫生紧急事件，在全球范围内造成了巨大的压力和生命损失。病毒刺突糖蛋白是一种关键分子，通过与人类 ACE2 相互作用介导 SARS-CoV-2 的传播。然而，在大流行过程中，尚未对刺突蛋白突变进行彻底分析，也没有分析这些突变体如何影响 SARS-CoV-2 的传播。此外，已经报道了宠物和野生动物感染 SARS-CoV-2 的病例，因此需要对这些动物的易感性进行深入研究，因为它们也可能与 SARS-CoV-2 在传播给人类之前的可能中间宿主有关。在获得超过 226000 个 SARS-CoV-2 序列后，我们在刺突基因中发现了 1573 个错义突变，其中 226 个位于直接与人类 ACE2 相互作用的受体结合域（RBD）区域内。对 SARS-CoV-2 刺突突变体与 ACE2 分子之间相互作用的建模表明，在相互作用界面的 RBD 区域中，大多数 74 个错义突变对刺突与 ACE2 的结合几乎没有影响，而 RBD 中的几个突变增加了对人类 ACE2 的结合亲和力，从而使病毒更具传染性。另一方面，对动物 ACE2 分子与 SARS-CoV-2 刺突之间相互作用的建模表明，许多宠物和野生动物的 ACE2 具有不同的结合能力。特别是，竹鼠的 ACE2 与 SARS-CoV-2 刺突蛋白具有更强的结合能力，而鼹鼠、田鼠、Mus pahari、果子狸和穿山甲的 ACE2 与人类 ACE2 的结合能力较弱。我们的研究结果为 SARS-CoV-2 刺突突变体与人类 ACE2 相互作用的影响提供了结构见解，并阐明了 SARS-CoV-2 在宠物和野生动物中的传播情况，以及 SARS-CoV-2 中间宿主的可能线索。
