Zhou Zhonghua, Yang Ziyi, Ou Junxian, Zhang Hong, Zhang Qiwei, Dong Ming, Zhang Gong
MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China.
Comput Struct Biotechnol J. 2021;19:161-167. doi: 10.1016/j.csbj.2020.12.005. Epub 2020 Dec 16.
The SARS-CoV-2 virus and its homolog SARS-CoV penetrate human cells by binding of viral spike protein and human angiotensin converting enzyme II (ACE2). SARS-CoV causes high fever in almost all patients, while SARS-CoV-2 does not. Moreover, analysis of the clinical data revealed that the higher body temperature is a protective factor in COVID-19 patients, making us to hypothesize a temperature-dependent binding affinity of SARS-CoV-2 to human ACE2 receptor. In this study, our molecular dynamics simulation and protein surface plasmon resonance cohesively proved the SARS-CoV-2-ACE2 binding was less affinitive and stable under 40 °C (~18 nM) than the optimum temperature 37 °C (6.2 nM), while SARS-CoV-ACE2 binding was not (6.4 nM vs. 8.5 nM), which evidenced the temperature-dependent affinity and explained that higher temperature is related to better clinical outcome. The decreased infection at higher temperature was also validated by pseudovirus entry assay using Vero and Caco-2 cells. We also demonstrated the structural basis of the distinct temperature-dependence of the two coronaviruses. Furthermore, the meta-analysis revealed a milder inflammatory response happened in the early stage of COVID-19, which explained the low fever tendency of COVID-19 and indicated the co-evolution of the viral protein structure and the inflammatory response. The temperature dependence of the binding affinity also indicated that higher body temperature at early stages might be beneficial to the COVID-19 patients.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）病毒及其同源物 SARS-CoV 通过病毒刺突蛋白与人血管紧张素转换酶 II（ACE2）结合来侵入人体细胞。SARS-CoV 几乎使所有患者出现高热，而 SARS-CoV-2 则不然。此外，临床数据分析显示，较高体温是 COVID-19 患者的一个保护因素，这使我们推测 SARS-CoV-2 与人 ACE2 受体的结合亲和力存在温度依赖性。在本研究中，我们的分子动力学模拟和蛋白质表面等离子体共振一致证明，与最佳温度 37°C（6.2 nM）相比，SARS-CoV-2-ACE2 在 40°C（~18 nM）下的结合亲和力较低且稳定性较差，而 SARS-CoV-ACE2 的结合则没有这种情况（6.4 nM 对 8.5 nM），这证明了结合亲和力的温度依赖性，并解释了较高温度与更好的临床结果相关。使用 Vero 和 Caco-2 细胞的假病毒进入试验也验证了较高温度下感染率的降低。我们还展示了两种冠状病毒不同温度依赖性的结构基础。此外，荟萃分析显示 COVID-19 早期发生的炎症反应较轻，这解释了 COVID-19 的低热倾向，并表明了病毒蛋白结构与炎症反应的共同进化。结合亲和力的温度依赖性还表明，早期较高体温可能对 COVID-19 患者有益。
