Electrostatic Interactions Are the Primary Determinant of the Binding Affinity of SARS-CoV-2 Spike RBD to ACE2: A Computational Case Study of Omicron Variants
To explore the mechanistic origin that determines the binding affinity of SARS-CoV-2 spike receptor binding domain (RBD) to human angiotensin converting enzyme 2 (ACE2), we constructed the homology models of RBD-ACE2 complexes of four Omicron subvariants (BA.1, BA.2, BA.3 and BA.4/5), and compared t...
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| Format: | Article |
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/23/14796 |
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| author | Peng Sang Yong-Qin Chen Meng-Ting Liu Yu-Ting Wang Ting Yue Yi Li Yi-Rui Yin Li-Quan Yang |
| author_facet | Peng Sang Yong-Qin Chen Meng-Ting Liu Yu-Ting Wang Ting Yue Yi Li Yi-Rui Yin Li-Quan Yang |
| author_sort | Peng Sang |
| collection | DOAJ |
| description | To explore the mechanistic origin that determines the binding affinity of SARS-CoV-2 spike receptor binding domain (RBD) to human angiotensin converting enzyme 2 (ACE2), we constructed the homology models of RBD-ACE2 complexes of four Omicron subvariants (BA.1, BA.2, BA.3 and BA.4/5), and compared them with wild type complex (RBD<sub>WT</sub>-ACE2) in terms of various structural dynamic properties by molecular dynamics (MD) simulations and binding free energy (BFE) calculations. The results of MD simulations suggest that the RBDs of all the Omicron subvariants (RBD<sub>OMI</sub>s) feature increased global structural fluctuations when compared with RBD<sub>WT</sub>. Detailed comparison of BFE components reveals that the enhanced electrostatic attractive interactions are the main determinant of the higher ACE2-binding affinity of RBD<sub>OMI</sub>s than RBD<sub>WT</sub>, while the weakened electrostatic attractive interactions determine RBD of BA.4/5 subvariant (RBD<sub>BA.4/5</sub>) lowest ACE2-binding affinity among all Omicron subvariants. The per-residue BFE decompositions and the hydrogen bond (HB) networks analyses indicate that the enhanced electrostatic attractive interactions are mainly through gain/loss of the positively/negatively charged residues, and the formation or destruction of the interfacial HBs and salt bridges can also largely affect the ACE2-binding affinity of RBD. It is worth pointing out that since Q493R plays the most important positive contribution in enhancing binding affinity, the absence of this mutation in RBD<sub>BA.4/5</sub> results in a significantly weaker binding affinity to ACE2 than other Omicron subvariants. Our results provide insight into the role of electrostatic interactions in determining of the binding affinity of SARS-CoV-2 RBD to human ACE2. |
| first_indexed | 2024-03-09T17:46:32Z |
| format | Article |
| id | doaj.art-7172ab19b4e747dabe154c6829ad131c |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T17:46:32Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-7172ab19b4e747dabe154c6829ad131c2023-11-24T11:07:59ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123231479610.3390/ijms232314796Electrostatic Interactions Are the Primary Determinant of the Binding Affinity of SARS-CoV-2 Spike RBD to ACE2: A Computational Case Study of Omicron VariantsPeng Sang0Yong-Qin Chen1Meng-Ting Liu2Yu-Ting Wang3Ting Yue4Yi Li5Yi-Rui Yin6Li-Quan Yang7College of Agriculture and Biological Science, Dali University, Dali 671000, ChinaCollege of Agriculture and Biological Science, Dali University, Dali 671000, ChinaCollege of Agriculture and Biological Science, Dali University, Dali 671000, ChinaCollege of Agriculture and Biological Science, Dali University, Dali 671000, ChinaCollege of Agriculture and Biological Science, Dali University, Dali 671000, ChinaCollege of Mathematics and Computer Science, Dali University, Dali 671000, ChinaCollege of Agriculture and Biological Science, Dali University, Dali 671000, ChinaCollege of Agriculture and Biological Science, Dali University, Dali 671000, ChinaTo explore the mechanistic origin that determines the binding affinity of SARS-CoV-2 spike receptor binding domain (RBD) to human angiotensin converting enzyme 2 (ACE2), we constructed the homology models of RBD-ACE2 complexes of four Omicron subvariants (BA.1, BA.2, BA.3 and BA.4/5), and compared them with wild type complex (RBD<sub>WT</sub>-ACE2) in terms of various structural dynamic properties by molecular dynamics (MD) simulations and binding free energy (BFE) calculations. The results of MD simulations suggest that the RBDs of all the Omicron subvariants (RBD<sub>OMI</sub>s) feature increased global structural fluctuations when compared with RBD<sub>WT</sub>. Detailed comparison of BFE components reveals that the enhanced electrostatic attractive interactions are the main determinant of the higher ACE2-binding affinity of RBD<sub>OMI</sub>s than RBD<sub>WT</sub>, while the weakened electrostatic attractive interactions determine RBD of BA.4/5 subvariant (RBD<sub>BA.4/5</sub>) lowest ACE2-binding affinity among all Omicron subvariants. The per-residue BFE decompositions and the hydrogen bond (HB) networks analyses indicate that the enhanced electrostatic attractive interactions are mainly through gain/loss of the positively/negatively charged residues, and the formation or destruction of the interfacial HBs and salt bridges can also largely affect the ACE2-binding affinity of RBD. It is worth pointing out that since Q493R plays the most important positive contribution in enhancing binding affinity, the absence of this mutation in RBD<sub>BA.4/5</sub> results in a significantly weaker binding affinity to ACE2 than other Omicron subvariants. Our results provide insight into the role of electrostatic interactions in determining of the binding affinity of SARS-CoV-2 RBD to human ACE2.https://www.mdpi.com/1422-0067/23/23/14796SARS-CoV-2OmicronRBDACE2binding affinityelectrostatic interactions |
| spellingShingle | Peng Sang Yong-Qin Chen Meng-Ting Liu Yu-Ting Wang Ting Yue Yi Li Yi-Rui Yin Li-Quan Yang Electrostatic Interactions Are the Primary Determinant of the Binding Affinity of SARS-CoV-2 Spike RBD to ACE2: A Computational Case Study of Omicron Variants International Journal of Molecular Sciences SARS-CoV-2 Omicron RBD ACE2 binding affinity electrostatic interactions |
| title | Electrostatic Interactions Are the Primary Determinant of the Binding Affinity of SARS-CoV-2 Spike RBD to ACE2: A Computational Case Study of Omicron Variants |
| title_full | Electrostatic Interactions Are the Primary Determinant of the Binding Affinity of SARS-CoV-2 Spike RBD to ACE2: A Computational Case Study of Omicron Variants |
| title_fullStr | Electrostatic Interactions Are the Primary Determinant of the Binding Affinity of SARS-CoV-2 Spike RBD to ACE2: A Computational Case Study of Omicron Variants |
| title_full_unstemmed | Electrostatic Interactions Are the Primary Determinant of the Binding Affinity of SARS-CoV-2 Spike RBD to ACE2: A Computational Case Study of Omicron Variants |
| title_short | Electrostatic Interactions Are the Primary Determinant of the Binding Affinity of SARS-CoV-2 Spike RBD to ACE2: A Computational Case Study of Omicron Variants |
| title_sort | electrostatic interactions are the primary determinant of the binding affinity of sars cov 2 spike rbd to ace2 a computational case study of omicron variants |
| topic | SARS-CoV-2 Omicron RBD ACE2 binding affinity electrostatic interactions |
| url | https://www.mdpi.com/1422-0067/23/23/14796 |
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