Identifying the Zoonotic Origin of SARS-CoV-2 by Modeling the Binding Affinity between the Spike Receptor-Binding Domain and Host ACE2
Identifying the Zoonotic Origin of SARS-CoV-2 by Modeling the Binding Affinity between the Spike Receptor-Binding Domain and Host ACE2
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DOI：
10.1021/acs.jproteome.0c00717
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发表时间：
2020-12-04
影响因子：
4.4
通讯作者：
Zhang, Yang
中科院分区：
文献类型：
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作者：
Huang, Xiaoqiang;Zhang, Chengxin;Zhang, Yang
尽管对SARS-CoV-2的研究取得了相当大的进展，但该病毒的直接人畜共患起源（中间宿主）仍然不明确。鉴定中间宿主的最确定的方法是在野生动物中检测SARS-CoV-2样冠状病毒。然而，由于动物物种数量众多，在实验室中筛选所有物种是不可行的。鉴于与ACE 2蛋白的结合是冠状病毒入侵宿主细胞的第一步，我们提出了一个计算管道，通过模拟刺突受体结合结构域（RBD）和宿主ACE 2之间的结合亲和力来识别SARS-CoV-2的潜在中间宿主。使用这个管道，我们系统地检查了来自哺乳动物、鸟类、鱼类、爬行动物和两栖动物的285种ACE 2变体，发现为模拟的Spike-RBD/ACE 2复合物结构计算的结合能与动物感染的有效性密切相关，如由多个实验数据集确定的。基于优化的结合亲和力截止值，我们提出了一组96种哺乳动物，包括48种实验研究的哺乳动物，它们对SARS-CoV-2是允许的，其中来自灵长类动物、啮齿类动物和食肉动物的候选者感染风险最高。总的来说，这项工作不仅为进一步的实验研究提供了有限的潜在中间SARS-CoV-2宿主，而且更重要的是，它提出了一种新的基于结构的方法来进行一般人畜共患病的起源和易感性分析，这对人类传染病控制和野生动物保护至关重要。
Despite considerable research progress on SARS-CoV-2, the direct zoonotic origin (intermediate host) of the virus remains ambiguous. The most definitive approach to identify the intermediate host would be the detection of SARS-CoV-2-like coronaviruses in wild animals. However, due to the high number of animal species, it is not feasible to screen all the species in the laboratory. Given that binding to ACE2 proteins is the first step for the coronaviruses to invade host cells, we propose a computational pipeline to identify potential intermediate hosts of SARS-CoV-2 by modeling the binding affinity between the Spike receptor-binding domain (RBD) and host ACE2. Using this pipeline, we systematically examined 285 ACE2 variants from mammals, birds, fish, reptiles, and amphibians, and found that the binding energies calculated for the modeled Spike-RBD/ACE2 complex structures correlated closely with the effectiveness of animal infection as determined by multiple experimental data sets. Built on the optimized binding affinity cutoff, we suggest a set of 96 mammals, including 48 experimentally investigated ones, which are permissive to SARS-CoV-2, with candidates from primates, rodents, and carnivores at the highest risk of infection. Overall, this work not only suggests a limited range of potential intermediate SARS-CoV-2 hosts for further experimental investigation, but also, more importantly, it proposes a new structure-based approach to general zoonotic origin and susceptibility analyses that are critical for human infectious disease control and wildlife protection.