The Impact of Mutation Sets in Receptor-Binding Domain of SARS-CoV-2 Variants on Stability of the RBD–ACE2 Complex

Abstract

Aim: Bioinformatic analysis of mutation sets in receptor-binding domain (RBD) of currently and previously circulating SARS-CoV-2 variants of concern (VOCs) and interest (VOIs) to assess their ability to bind the ACE2 receptor. Methods:In silico sequence and structure-oriented approaches were used to evaluate the impact of single and multiple mutations. Results: Mutations detected in VOCs and VOIs led to the reduction of binding free energy of the RBD–ACE2 complex, forming additional chemical bonds with ACE2, and to an increase of RBD–ACE2 complex stability. Conclusion: Mutation sets characteristic of SARS-CoV-2 variants have complex effects on the ACE2 receptor-binding affinity associated with amino acid interactions at mutation sites, as well as on the acquisition of other viral adaptive advantages.

Plain language summary

The increase in the infectious potential of SARS-CoV-2 variants (Alpha, Beta, Gamma, Delta, Omicron, etc.) that causes COVID-19 is mainly caused by virus mutations. Particularly important for the development of the disease is the interaction of the coronavirus spike protein with a receptor on the surface of human cell, as a result of which the virus penetrates the cell. Angiotensin-binding enzyme (ACE2) is such a receptor in humans, and there is a receptor-binding domain (RBD) in the coronavirus spike protein. In this study, using bioinformatic methods, an analysis of mutations in the RBD of the virus was carried out to find out their influence on the functionality and ability of the virus to interact with the ACE2 receptor with high stability, which ultimately leads to infection. A number of mutations increase the infectious potential of the virus. More recent variants of the virus have more than one mutation in the RBD, so their effects are complex. It is important that the coronavirus is constantly evolving, increasing the ability to bind to the ACE2 receptor, as well as avoiding the immune response. The Omicron variant, which has at least 15 mutations in the RBD, is the most successful in these directions.

Tweetable abstract

Mutation sets in the RBD of SARS-CoV-2 variants have complex effects on the ACE2 receptor-binding affinity.

Keywords::

• bioinformatic analysis
• RBD–ACE2 complex
• receptor binding
• SARS-CoV-2 variants
• single and multiple mutations
• spike protein

Author contributions

M Peka and V Balatsky were responsible for study conception and design; M Peka was responsible for conducting in silico experiments; M Peka and V Balatsky were responsible for data analysis, drafting and revision of the manuscript.

Financial & competing interests disclosure

This work was supported by the National Academy of Agrarian Sciences of Ukraine. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

This work was supported by the National Academy of Agrarian Sciences of Ukraine. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.