Dissecting Binding and Immune Evasion Mechanisms for Ultrapotent Class I and Class 4/1 Neutralizing Antibodies of SARS-CoV-2 Spike Protein Using a Multi-Pronged Computational Approach

Authors

Mohammed Alshahrani, Chapman UniversityFollow
Vedant Parikh, Chapman University
Brandon Foley, Chapman UniversityFollow
Gennady M. Verkhivker, Chapman UniversityFollow

Document Type

Article

Publication Date

1-26-2026

Abstract

The relentless evolution of SARS-CoV-2 underscores the urgent need to decipher the molecular principles that enable certain antibodies to maintain exceptional breadth and resilience against immune escape. In this study, we employ a multi-pronged computational framework integrating structural analysis, conformational dynamics, mutational scanning, MM-GBSA binding energetics, and conformational/mutational frustration profiling to dissect the mechanisms of ultrapotent neutralization by a cohort of broadly reactive Class 1 antibodies (BD55-1205, 19-77, ZCP4C9, ZCP3B4) and the Class 4/1 antibody ADG20. We reveal a unifying biophysical architecture: these antibodies bind via rigid, pre-configured interfaces that distribute binding energy across extensive epitopes through numerous suboptimal yet synergistic interactions, predominantly with backbone atoms and conserved side chains. This distributed redundancy enables tolerance to mutations at key sites like F456L or A475V without catastrophic loss of affinity. Mutational scanning identifies a hierarchical hotspot organization where primary hotspots (e.g., H505, Y501, Y489, Y421)—which overlap with ACE2-contact residues and incur high fitness costs upon mutation—are buffered by secondary hotspots (e.g., F456, L455) that are more permissive to variation. MM-GBSA energy decomposition confirms that van der Waals-driven hydrophobic packing dominates binding, with primary hotspots contributing disproportionately to affinity, while electrostatic networks provide auxiliary stabilization that mitigates mutational effects. Critically, both conformational and mutational frustration analyses demonstrate that immune escape hotspots reside in neutral-frustration “playgrounds” that permit mutational exploration without destabilizing the RBD, explaining the repeated emergence of convergent mutations across lineages. Our results establish that broad neutralization arises not from ultra-high-affinity anchors, but rather from strategic energy distribution across rigid, evolutionarily informed interfaces. By linking distributed binding, neutral frustration landscapes, and viral fitness constraints, this framework provides a predictive blueprint for designing next-generation therapeutics and vaccines capable of withstanding viral evolution.

Comments

This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Physical Chemistry Chemical Physics in 2026 following peer review. This article may not exactly replicate the final published version. The definitive publisher-authenticated version is available online at https://doi.org/10.1039/D5CP04209G.

This scholarship is part of the Chapman University COVID-19 Archives.

Recommended Citation

M. Alshahrani, V. Parikh, B. Foley and G. M. Verkhivker, Phys. Chem. Chem. Phys., 2026, https://doi.org/10.1039/D5CP04209G

Peer Reviewed

1

Copyright

Royal Society of Chemistry