Ensemble-Based Mutational Profiling and Network Analysis of the SARS-CoV-2 Spike Omicron XBB Lineages for Interactions with the ACE2 Receptor and Antibodies: Cooperation of Binding Hotspots in Mediating Epistatic Couplings Underlies Binding Mechanism and Immune Escape
Abstract
:1. Introduction
2. Results and Discussion
2.1. Evolutionary and Phylogenetic Analysis of Differences between BA.2 and XBB.1.5 Lineages
2.2. Mutational Profiling Analysis of Omicron Variants Identifies Key Identifies Universal and Variant-Specific Structural Stability and Binding Affinity Hotspots in the SARS-CoV-2 RBD Complexes with ACE2
2.3. Probing Epistatic Relationships in the XBB.1.5 and BQ.1.1 Variants Using Mutational Scanning
2.4. Network-Based Community Analysis of Epistatic Couplings in the RBD–ACE2 Complexes
2.5. Mutational Profiling of Spike Protein Binding with Monoclonal RBD Antibodies: Revealing Central Role of F456L and F486P Mutations in Immune Evasion
3. Materials and Methods
3.1. Structure Preparation and Molecular Dynamics Simulations
3.2. Mutational Scanning and Binding Free Energy Computations
3.3. Network-Based Community Analysis and Clique-Based Model of Epistatic Interactions
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Omicron Variant | Mutational Landscape |
---|---|
BA.1 | A67, T95I, G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K, L981F |
BA.2 | T19I, G142D, V213G, G339D, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, S477N, T478K, E484A, Q493R, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, N969K |
BA.4 | T19I, G142D, V213G, G339D, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, L452R, S477N, T478K, E484A, F486V, R493Q reversal, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, N969K |
BA.5 | T19I, LPPA24-27S, Del 69-70, G142D, V213G, G339D, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, L452R, S477N, T478K, E484A, F486V, R493Q reversal, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, N969K |
BQ.1.1 | T19I, LPPA24-27S, H69del, V70del, V213G, G142D, G339D, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, K444T, L452R, N460K, S477N, T478K, E484A, F486V, R493Q reversal, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, N969K |
XBB.1 | T19I, V83A, G142D, Del144, H146Q, Q183E, V213E, G252V, G339H, R346T, L368I, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, V445P, G446S, N460K, S477N, T478K, E484A, F486S, F490S, R493Q reversal, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, N969K |
XBB.1.5 | T19I, V83A, G142D, Del144, H146Q, Q183E, V213E, G252V, G339H, R346T, L368I, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, V445P, G446S, N460K, S477N, T478K, E484A, F486P, F490S, R493Q reversal, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, N969K |
XBB.1.5 + F456L | T19I, V83A, G142D, Del144, H146Q, Q183E, V213E, G252V, G339H, R346T, L368I, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, V445P, G446S, F456L, N460K, S477N, T478K, E484A, F486P, F490S, R493Q reversal, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, N969K |
XBB.1.5 + L455F/F456L | T19I, V83A, G142D, Del144, H146Q, Q183E, V213E, G252V, G339H, R346T, L368I, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, V445P, G446S, L455F, F456L, N460K, S477N, T478K, E484A, F486P, F490S, R493Q reversal, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, N969K |
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Raisinghani, N.; Alshahrani, M.; Gupta, G.; Verkhivker, G. Ensemble-Based Mutational Profiling and Network Analysis of the SARS-CoV-2 Spike Omicron XBB Lineages for Interactions with the ACE2 Receptor and Antibodies: Cooperation of Binding Hotspots in Mediating Epistatic Couplings Underlies Binding Mechanism and Immune Escape. Int. J. Mol. Sci. 2024, 25, 4281. https://doi.org/10.3390/ijms25084281
Raisinghani N, Alshahrani M, Gupta G, Verkhivker G. Ensemble-Based Mutational Profiling and Network Analysis of the SARS-CoV-2 Spike Omicron XBB Lineages for Interactions with the ACE2 Receptor and Antibodies: Cooperation of Binding Hotspots in Mediating Epistatic Couplings Underlies Binding Mechanism and Immune Escape. International Journal of Molecular Sciences. 2024; 25(8):4281. https://doi.org/10.3390/ijms25084281
Chicago/Turabian StyleRaisinghani, Nishank, Mohammed Alshahrani, Grace Gupta, and Gennady Verkhivker. 2024. "Ensemble-Based Mutational Profiling and Network Analysis of the SARS-CoV-2 Spike Omicron XBB Lineages for Interactions with the ACE2 Receptor and Antibodies: Cooperation of Binding Hotspots in Mediating Epistatic Couplings Underlies Binding Mechanism and Immune Escape" International Journal of Molecular Sciences 25, no. 8: 4281. https://doi.org/10.3390/ijms25084281
APA StyleRaisinghani, N., Alshahrani, M., Gupta, G., & Verkhivker, G. (2024). Ensemble-Based Mutational Profiling and Network Analysis of the SARS-CoV-2 Spike Omicron XBB Lineages for Interactions with the ACE2 Receptor and Antibodies: Cooperation of Binding Hotspots in Mediating Epistatic Couplings Underlies Binding Mechanism and Immune Escape. International Journal of Molecular Sciences, 25(8), 4281. https://doi.org/10.3390/ijms25084281