Does SARS-CoV-2 Bind to Human ACE2 More Strongly Than Does SARS-CoV?
Does SARS-CoV-2 Bind to Human ACE2 More Strongly Than Does SARS-CoV?
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DOI：
10.1021/acs.jpcb.0c04511
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发表时间：
2020-08-27
影响因子：
3.3
通讯作者：
Li, Mai Suan
中科院分区：
文献类型：
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作者：
Hoang Linh Nguyen;Pham Dang Lan;Li, Mai Suan
2019年12月在中国武汉首次报告的2019年新型冠状病毒（SARS-CoV-2）疫情于2020年3月被世界卫生组织宣布为大流行。SARS-CoV-2在基因上与SARS-CoV密切相关，后者在2002年至2003年期间在超过25个国家造成了8096例确诊病例的全球流行。鉴于发病率和死亡率很高，目前的大流行对全人类构成了危险，促使我们在原子水平上了解SARS-CoV-2的活动。实验研究表明，SARS-CoV-2和SARS-CoV的刺突蛋白在进入细胞复制之前与血管紧张素转换酶2（ACE 2）结合。然而，不同团体报告的结合亲和力似乎相互矛盾。Wrapp等（Science 2020，367，1260-1263）显示SARS-CoV-2的刺突蛋白比SARS-CoV更强地结合ACE 2肽酶结构域（ACE 2-PD），并且这一事实可能与新病毒的更严重性相关。然而，Walls等（Cell 2020，181，281-292）报道SARS-CoV-2表现出更高的结合亲和力，但两种变体之间的差异相对较小。为了了解结合机制和实验结果，我们研究了SARS-CoV-RBD和SARS-CoV-2-RBD的受体结合结构域（RBD）如何与人ACE 2-PD相互作用。我们应用粗粒度模型计算解离常数，发现SARS-CoV-2显示出2倍高的结合亲和力。使用操纵的全原子分子动力学模拟，我们证明，像一个粗粒度的模拟，SARS-CoV-2-RBD与ACE 2-PD更强的SARS-CoV-RBD，证明了更高的断裂力和更大的拉动工作。我们表明，这两种病毒的结合亲和力ACE 2是由静电相互作用。
The 2019 novel coronavirus (SARS-CoV-2) epidemic, which was first reported in December 2019 in Wuhan, China, was declared a pandemic by the World Health Organization in March 2020. Genetically, SARS-CoV-2 is closely related to SARS-CoV, which caused a global epidemic with 8096 confirmed cases in more than 25 countries from 2002 to 2003. Given the significant morbidity and mortality rate, the current pandemic poses a danger to all of humanity, prompting us to understand the activity of SARS-CoV-2 at the atomic level. Experimental studies have revealed that spike proteins of both SARS-CoV-2 and SARS-CoV bind to angiotensin-converting enzyme 2 (ACE2) before entering the cell for replication. However, the binding affinities reported by different groups seem to contradict each other. Wrapp et al. (Science 2020, 367, 1260-1263) showed that the spike protein of SARS-CoV-2 binds to the ACE2 peptidase domain (ACE2-PD) more strongly than does SARS-CoV, and this fact may be associated with a greater severity of the new virus. However, Walls et al. (Cell 2020, 181, 281-292) reported that SARS-CoV-2 exhibits a higher binding affinity, but the difference between the two variants is relatively small. To understand the binding mechnism and experimental results, we investigated how the receptor binding domain (RBD) of SARS-CoV (SARS-CoV-RBD) and SARS-CoV-2 (SARS-CoV-2-RBD) interacts with a human ACE2-PD using molecular modeling. We applied a coarse-grained model to calculate the dissociation constant and found that SARS-CoV-2 displays a 2-fold higher binding affinity. Using steered all-atom molecular dynamics simulations, we demonstrate that, like a coarse-grained simulation, SARS-CoV-2-RBD was associated with ACE2-PD more strongly than was SARS-CoV-RBD, as evidenced by a higher rupture force and larger pulling work. We show that the binding affinity of both viruses to ACE2 is driven by electrostatic interactions.