Temperature dependence of the SARS-CoV-2 affinity to human ACE2 determines COVID-19 progression and clinical outcome

Zhonghua Zhou; Ziyi Yang; Junxian Ou; Hong Zhang; Qiwei Zhang; Ming Dong; Gong Zhang

doi:10.1016/j.csbj.2020.12.005

Temperature dependence of the SARS-CoV-2 affinity to human ACE2 determines COVID-19 progression and clinical outcome

Comput Struct Biotechnol J. 2021:19:161-167. doi: 10.1016/j.csbj.2020.12.005. Epub 2020 Dec 16.

Authors

Zhonghua Zhou¹, Ziyi Yang^{2

3}, Junxian Ou⁴, Hong Zhang^{2

3}, Qiwei Zhang^{4

5}, Ming Dong^{2

3}, Gong Zhang^{1

3}

Affiliations

¹ 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.
² Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China.
³ Chi-Biotech Co. Ltd., Shenzhen 518023, China.
⁴ Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong 510515, China.
⁵ Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, Guangdong 510632, China.

Abstract

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.

Keywords: Affinity; COVID-19; SARS-CoV-2; Spike protein; Structural basis; Temperature dependence.