Document Type
Article
Publication Date
5-22-2025
Abstract
In this study, we conducted a comprehensive analysis of the interactions between the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and four neutralizing antibodies—S309, S304, CYFN1006, and VIR-7229. Using integrative computational modeling that combined all-atom molecular dynamics (MD) simulations, mutational scanning, and MM-GBSA binding free energy calculations, we elucidated the structural, energetic, and dynamic determinants of antibody binding. Our findings reveal distinct dynamic binding mechanisms and evolutionary adaptation driving the broad neutralization effect of these antibodies. We show that S309 targets conserved residues near the ACE2 interface, leveraging synergistic van der Waals and electrostatic interactions, while S304 focuses on fewer but sensitive residues, making it more susceptible to escape mutations. The analysis of CYFN-1006.1 and CYFN-1006.2 antibody binding highlights broad epitope coverage with critical anchors at T345, K440, and T346, enhancing its efficacy against variants carrying the K356T mutation, which caused escape from S309 binding. Our analysis of broadly potent VIR-7229 antibody binding to XBB.1.5 and EG.5 Omicron variants emphasized a large and structurally complex epitope, demonstrating certain adaptability and compensatory effects to F456L and L455S mutations. Mutational profiling identified key residues crucial for antibody binding, including T345, P337, and R346 for S309 as well as T385 and K386 for S304, underscoring their roles as evolutionary “weak spots” that balance viral fitness and immune evasion. The results of the energetic analysis demonstrate a good agreement between the predicted binding hotspots, reveal distinct energetic mechanisms of binding, and highlight the importance of targeting conserved residues and diverse epitopes to counteract viral resistance.
Recommended Citation
Alshahrani, M.; Parikh, V.; Foley, B.; Verkhivker, G. Integrative Computational Modeling of Distinct Binding Mechanisms for Broadly Neutralizing Antibodies Targeting SARS-CoV-2 Spike Omicron Variants: Balance of Evolutionary and Dynamic Adaptability in Shaping Molecular Determinants of Immune Escape. Viruses 2025, 17, 741. https://doi.org/10.3390/v17060741
Supplementary materials. Figure S1 presents structural details of the binding interfaces for SARS-CoV-2-RBD complexes with antibodies S309, S304, CYFN-1006.1/CYFN-1006.2, and VIR-7229. Figure S2 presents structural organization of the SARS-CoV-2-RBD complexes with CYFN-1006.1, CYFN-1006.2, and VIR-7229 antibodies. Datasets S1–S4 present the results of mutational scanning for different S309-RBD complexes. Datasets S5–S8 present the results of mutational scanning for different S304-RBD complexes. Datasets S9 and S10 present the results of mutational scanning for RBD complexes with CYFN-100.1 and CYFN-1006.2 antibodies. Datasets S11 and S12 present the results of mutational scanning for VIR-7229 binding with XBB.1.5 RBD and EG.5 RBD, respectively. Table S1 highlights the mutational landscape for Omicron variants explored in this study. Tables S2–S5 present the results of MM-GBSA computations for different S309-RBD complexes. Table S6 presents the results of MM-GBSA computations for S304-RBD complex. Tables S7 and S8 present the results of MM-GBSA computations for RBD complexes with CYFN-1006.1 and CYFN.1006-2, respectively. Tables S9 and S10 present the results of MM-GBSA computations for VIR-7229 complexes with XBB.1.5 RBD and EG.5 RBD. Table S11 presents a comparative analysis of the conservation status and mutation frequency of key epitope residues targeted by the four broadly neutralizing antibodies studied. Table S12 summarizes the major observations and highlights differences in the epitopes, dynamics, binding mechanisms, binding hotspots, and escape resistance profiles for the examined antibodies.
Peer Reviewed
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The authors
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Comments
This article was originally published in Viruses, volume 17, in 2025. https://doi.org/10.3390/v17060741
This scholarship is part of the Chapman University COVID-19 Archives.