PT  - JOURNAL ARTICLE
AU  - Shaolei Teng
AU  - Adebiyi Sobitan
AU  - Raina Rhoades
AU  - Dongxiao Liu
AU  - Qiyi Tang
TI  - Systemic Effects of Missense Mutations on SARS-CoV-2 Spike Glycoprotein Stability and Receptor Binding Affinity
AID  - 10.1101/2020.05.21.109835
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.21.109835
4099  - http://biorxiv.org/content/early/2020/05/23/2020.05.21.109835.short
4100  - http://biorxiv.org/content/early/2020/05/23/2020.05.21.109835.full
AB  - The spike (S) glycoprotein of SARS-CoV-2 is responsible for the binding to the permissive cells. The receptor-binding domain (RBD) of SARS-CoV-2 S protein directly interacts with the human angiotensin-converting enzyme 2 (ACE2) on the host cell membrane. In this study, we used computational saturation mutagenesis approaches, including structure-based energy calculations and sequence-based pathogenicity predictions, to quantify the systemic effects of missense mutations on SARS-CoV-2 S protein structure and function. A total of 18,354 mutations in S protein were analyzed and we discovered that most of these mutations could destabilize the entire S protein and its RBD. Specifically, residues G431 and S514 in SARS-CoV-2 RBD are important for S protein stability. We analyzed 384 experimentally verified S missense variations and revealed that the dominant pandemic form, D614G, can stabilize the entire S protein. Moreover, many mutations in N-linked glycosylation sites can increase the stability of the S protein. In addition, we investigated 3,705 mutations in SARS-CoV-2 RBD and 11,324 mutations in human ACE2 and found that SARS-CoV-2 neighbor residues G496 and F497 and ACE2 residues D355 and Y41 are critical for the RBD-ACE2 interaction. The findings comprehensively provide potential target sites in the development of drugs and vaccines against COVID-19.Competing Interest StatementThe authors have declared no competing interest.