Improved Binding Affinity of Omicron’s Spike Protein for the Human Angiotensin-Converting Enzyme 2 Receptor Is the Key behind Its Increased Virulence
The new variant of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), Omicron, has been quickly spreading in many countries worldwide. Compared to the original virus, Omicron is characterized by several mutations in its genomic region, including the spike protein’s receptor-binding d...
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| Format: | Article |
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MDPI AG
2022-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/6/3409 |
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| author | Rajender Kumar Natarajan Arul Murugan Vaibhav Srivastava |
| author_facet | Rajender Kumar Natarajan Arul Murugan Vaibhav Srivastava |
| author_sort | Rajender Kumar |
| collection | DOAJ |
| description | The new variant of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), Omicron, has been quickly spreading in many countries worldwide. Compared to the original virus, Omicron is characterized by several mutations in its genomic region, including the spike protein’s receptor-binding domain (RBD). We have computationally investigated the interaction between the RBD of both the wild type and Omicron variant of SARS-CoV-2 with the human angiotensin-converting enzyme 2 (hACE2) receptor using molecular dynamics and molecular mechanics-generalized Born surface area (MM-GBSA)-based binding free energy calculations. The mode of the interaction between Omicron’s RBD with the hACE2 receptor is similar to the original SARS-CoV-2 RBD except for a few key differences. The binding free energy difference shows that the spike protein of Omicron has an increased affinity for the hACE2 receptor. The mutated residues in the RBD showed strong interactions with a few amino acid residues of hACE2. More specifically, strong electrostatic interactions (salt bridges) and hydrogen bonding were observed between R493 and R498 residues of the Omicron RBD with D30/E35 and D38 residues of the hACE2, respectively. Other mutated amino acids in the Omicron RBD, e.g., S496 and H505, also exhibited hydrogen bonding with the hACE2 receptor. A pi-stacking interaction was also observed between tyrosine residues (RBD-Tyr501: hACE2-Tyr41) in the complex, which contributes majorly to the binding free energies and suggests that this is one of the key interactions stabilizing the formation of the complex. The resulting structural insights into the RBD:hACE2 complex, the binding mode information within it, and residue-wise contributions to the free energy provide insight into the increased transmissibility of Omicron and pave the way to design and optimize novel antiviral agents. |
| first_indexed | 2024-03-09T19:40:47Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T19:40:47Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c4c982e7dac041559b675a14cf791a022023-11-24T01:39:15ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-03-01236340910.3390/ijms23063409Improved Binding Affinity of Omicron’s Spike Protein for the Human Angiotensin-Converting Enzyme 2 Receptor Is the Key behind Its Increased VirulenceRajender Kumar0Natarajan Arul Murugan1Vaibhav Srivastava2Division of Glycoscience, Department of Chemistry, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, AlbaNova University Center, 106 91 Stockholm, SwedenDepartment of Computer Science, School of Electrical Engineering and Computer Science, KTH Royal Institute of Technology, 100 44 Stockholm, SwedenDivision of Glycoscience, Department of Chemistry, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, AlbaNova University Center, 106 91 Stockholm, SwedenThe new variant of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), Omicron, has been quickly spreading in many countries worldwide. Compared to the original virus, Omicron is characterized by several mutations in its genomic region, including the spike protein’s receptor-binding domain (RBD). We have computationally investigated the interaction between the RBD of both the wild type and Omicron variant of SARS-CoV-2 with the human angiotensin-converting enzyme 2 (hACE2) receptor using molecular dynamics and molecular mechanics-generalized Born surface area (MM-GBSA)-based binding free energy calculations. The mode of the interaction between Omicron’s RBD with the hACE2 receptor is similar to the original SARS-CoV-2 RBD except for a few key differences. The binding free energy difference shows that the spike protein of Omicron has an increased affinity for the hACE2 receptor. The mutated residues in the RBD showed strong interactions with a few amino acid residues of hACE2. More specifically, strong electrostatic interactions (salt bridges) and hydrogen bonding were observed between R493 and R498 residues of the Omicron RBD with D30/E35 and D38 residues of the hACE2, respectively. Other mutated amino acids in the Omicron RBD, e.g., S496 and H505, also exhibited hydrogen bonding with the hACE2 receptor. A pi-stacking interaction was also observed between tyrosine residues (RBD-Tyr501: hACE2-Tyr41) in the complex, which contributes majorly to the binding free energies and suggests that this is one of the key interactions stabilizing the formation of the complex. The resulting structural insights into the RBD:hACE2 complex, the binding mode information within it, and residue-wise contributions to the free energy provide insight into the increased transmissibility of Omicron and pave the way to design and optimize novel antiviral agents.https://www.mdpi.com/1422-0067/23/6/3409severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)Omicronhuman angiotensin-converting enzyme 2 (hACE2)molecular dynamics simulationreceptor-binding domain (RBD)receptor-binding motif (RBM) |
| spellingShingle | Rajender Kumar Natarajan Arul Murugan Vaibhav Srivastava Improved Binding Affinity of Omicron’s Spike Protein for the Human Angiotensin-Converting Enzyme 2 Receptor Is the Key behind Its Increased Virulence International Journal of Molecular Sciences severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) Omicron human angiotensin-converting enzyme 2 (hACE2) molecular dynamics simulation receptor-binding domain (RBD) receptor-binding motif (RBM) |
| title | Improved Binding Affinity of Omicron’s Spike Protein for the Human Angiotensin-Converting Enzyme 2 Receptor Is the Key behind Its Increased Virulence |
| title_full | Improved Binding Affinity of Omicron’s Spike Protein for the Human Angiotensin-Converting Enzyme 2 Receptor Is the Key behind Its Increased Virulence |
| title_fullStr | Improved Binding Affinity of Omicron’s Spike Protein for the Human Angiotensin-Converting Enzyme 2 Receptor Is the Key behind Its Increased Virulence |
| title_full_unstemmed | Improved Binding Affinity of Omicron’s Spike Protein for the Human Angiotensin-Converting Enzyme 2 Receptor Is the Key behind Its Increased Virulence |
| title_short | Improved Binding Affinity of Omicron’s Spike Protein for the Human Angiotensin-Converting Enzyme 2 Receptor Is the Key behind Its Increased Virulence |
| title_sort | improved binding affinity of omicron s spike protein for the human angiotensin converting enzyme 2 receptor is the key behind its increased virulence |
| topic | severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) Omicron human angiotensin-converting enzyme 2 (hACE2) molecular dynamics simulation receptor-binding domain (RBD) receptor-binding motif (RBM) |
| url | https://www.mdpi.com/1422-0067/23/6/3409 |
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