Mechanistic study of the transmission pattern of the SARS‐CoV‐2 omicron variant

Author:

An Ke123ORCID,Yang Xianzhi4,Luo Mengqi5,Yan Junfang12,Xu Peiyi12,Zhang Honghui12,Li Yuqing6,Wu Song6,Warshel Arieh7,Bai Chen123

Affiliation:

1. School of Life and Health Sciences, School of Medicine, The Chinese University of Hong Kong Shenzhen Guangdong China

2. Warshel Institute for Computational Biology Shenzhen China

3. Chenzhu (MoMeD) Biotechnology Co., Ltd Hangzhou Zhejiang China

4. Institute of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group) Shenzhen China

5. College of Management, Shenzhen University Shenzhen China

6. Department of Urology South China Hospital of Shenzhen University Shenzhen China

7. Department of Chemistry University of Southern California Los Angeles California USA

Abstract

AbstractThe omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) characterized by 30 mutations in its spike protein, has rapidly spread worldwide since November 2021, significantly exacerbating the ongoing COVID‐19 pandemic. In order to investigate the relationship between these mutations and the variant's high transmissibility, we conducted a systematic analysis of the mutational effect on spike–angiotensin‐converting enzyme‐2 (ACE2) interactions and explored the structural/energy correlation of key mutations, utilizing a reliable coarse‐grained model. Our study extended beyond the receptor‐binding domain (RBD) of spike trimer through comprehensive modeling of the full‐length spike trimer rather than just the RBD. Our free‐energy calculation revealed that the enhanced binding affinity between the spike protein and the ACE2 receptor is correlated with the increased structural stability of the isolated spike protein, thus explaining the omicron variant's heightened transmissibility. The conclusion was supported by our experimental analyses involving the expression and purification of the full‐length spike trimer. Furthermore, the energy decomposition analysis established those electrostatic interactions make major contributions to this effect. We categorized the mutations into four groups and established an analytical framework that can be employed in studying future mutations. Additionally, our calculations rationalized the reduced affinity of the omicron variant towards most available therapeutic neutralizing antibodies, when compared with the wild type. By providing concrete experimental data and offering a solid explanation, this study contributes to a better understanding of the relationship between theories and observations and lays the foundation for future investigations.

Funder

National Natural Science Foundation of China

National Science Foundation

National Institutes of Health

Publisher

Wiley

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