The continued evolution of SARS-CoV-2 has enabled an escape from most monoclonal antibodies, yet a subset of broadly neutralizing antibodies targeting three newly identified super-conserved RBD epitopes—SCORE-A, SCORE-B, and SCORE-C—retains remarkable activity against even the most recent JN.1-derived sublineages. Here, we employed an integrated computational framework combining conformational dynamics, mutational scanning, MM-GBSA binding energetics, and frustration profiling to dissect the molecular mechanisms by which XGI antibodies achieve broad neutralization and resistance to immune escape. Structural analysis revealed that all three SCORE epitopes share a common architecture: a highly conserved, minimally frustrated core that provides stable anchoring, flanked by peripheral regions that accommodate antibody-specific variations. Conformational dynamics showed that SCORE-A antibodies (XGI-183) rigidify the lateral epitope while leaving the RBM partially mobile; SCORE-B antibodies (XGI-198, XGI-203) clamp the RBM apex, directly blocking ACE2; and SCORE-C antibodies (XGI-171) allosterically loosen the RBM loop, impairing receptor engagement indirectly. Mutational scanning identified a hierarchical hotspot organization where primary hotspots (e.g., K356, T500, Y380, T385) are evolutionarily constrained and minimally frustrated, while secondary hotspots (e.g., V503, Y508, S383) are neutrally frustrated and represent the principal sites of immune-driven mutations. MM-GBSA decomposition revealed that van der Waals-driven hydrophobic packing dominates binding, with electrostatic interactions providing auxiliary stabilization. Critically, frustration analysis demonstrated that immune escape hotspots reside precisely in zones of neutral frustration—“energetic playgrounds” that permit mutational exploration without destabilizing the RBD—while minimally frustrated cores are evolutionarily locked. The comparative analysis of conformational versus mutational frustration distributions revealed a unifying principle: aligned neutral frustration yields permissive, escape-prone interfaces; decoupling enables the targeting of constrained cores; and the convergence of minimal frustration in both distributions creates invulnerable interfaces. These findings establish that broad neutralization arises not from ultra-high-affinity anchors but from strategic energy distribution across rigid, evolutionarily informed interfaces, providing a roadmap for designing next-generation therapeutics that target the invulnerable cores of viral surface proteins.

The continued evolution of SARS-CoV-2 has enabled escape from most monoclonal antibodies, yet a subset of broadly neutralizing antibodies targeting three newly identified super-conserved RBD epitopes—SCORE-A, SCORE-B, and SCORE-C—retains remarkable activity against even the most recent JN.1-derived sublineages. Here we employed an integrated computational framework combining conformational dynamics, mutational scanning, MM-GBSA binding energetics, and frustration profiling to dissect the molecular mechanisms by which XGI antibodies achieve broad neutralization and resistance to immune escape. Structural analysis revealed that all three SCORE epitopes share a common architecture: a highly conserved, minimally frustrated core that provides stable anchoring, flanked by peripheral regions that accommodate antibody-specific variations. Conformational dynamics showed that SCORE-A antibodies (XGI-183) rigidify the lateral epitope while leaving the RBM partially mobile; SCORE-B antibodies (XGI-198, XGI-203) clamp the RBM apex, directly blocking ACE2; and SCORE-C antibodies (XGI-171) allosterically loosen the RBM loop, impairing receptor engagement indirectly. Mutational scanning identified a hierarchical hotspot organization where primary hotspots (e.g., K356, T500, Y380, T385) are evolutionarily constrained and minimally frustrated, while secondary hotspots (e.g., V503, Y508, S383) are neutrally frustrated and represent the principal sites of immune-driven mutations. MM-GBSA decomposition revealed that van der Waals-driven hydrophobic packing dominates binding, with electrostatic interactions providing auxiliary stabilization. Critically, frustration analysis demonstrated that immune escape hotspots reside precisely in zones of neutral frustration—"energetic playgrounds" that permit mutational explora-tion without destabilizing the RBD—while minimally frustrated cores are evolutionarily locked. The comparative analysis of conformational versus mutational frustration dis-tributions revealed a unifying principle: aligned neutral frustration yields permissive, escape-prone interfaces; decoupling enables targeting of constrained cores; and convergence of minimal frustration in both distributions creates invulnerable interfaces. These findings establish that broad neutralization arises not from ultra-high-affinity anchors but from strategic energy distribution across rigid, evolutionarily informed interfaces, providing a roadmap for designing next-generation therapeutics that target the invulnerable cores of viral surface proteins.

Broadly neutralizing antibodies targeting the silent face of the SARS-CoV-2 receptor-binding do-main (RBD) provide essential templates for pan-sarbecovirus therapeutics, yet the precise bio-physical mechanisms dictating their neutralization breadth, energetic propensities, and escape re-silience remain unresolved. By combining all-atom and coarse-grained molecular dynamics, systematic mutational scanning, rigorous MM-GBSA binding free energy analysis, and residue interaction network modeling we delineate the comparative structural, energetic, and allosteric signatures of Site V (CC25.4, CC25.43, CC25.56, 7D6, 6D6 ) and CR3022-site (Group 1: CC25.54, CC84.2, CC84.24) antibodies. We discover that these two classes by engaging spatially opposite faces of the RBD fold produce mutually exclusive energetic hotspot modules. Site V antibodies are anchored along a surface-exposed lateral ridge by residues R355, R357, R466, I468, F464, and K462, whereas CR3022-site antibodies engage a buried β-sheet-core module comprising R408, K378, C379, Y380, F377, and Q414. Remarkably, despite these distinct epitopes, both classes converge on an ultra-conserved paratope tyrosine triad (Y99, Y100, Y49), establishing a universal structural motif for silent-face recognition. Network centrality modeling demonstrates that Site V and CR3022-site antibodies modulate ACE2 receptor interface dynamics via distinct upstream allo-steric pathways that converge on shared RBM-loop relays at Y423, Y396, and F464. Crucially, in CR3022-site antibodies, binding free energy hotspots and allosteric communication hubs coincide directly within the structurally constrained β-sheet core. This enforces a dual-constraint mecha-nism where escape mutations inherently compromise viral fold integrity. Conversely, Site V binding hotspots and allosteric networks are structurally segregated, exposing cryptic allosteric liabilities where mutations at non-contact positions (F456, R509) dynamically rewire network communication to impair neutralization without altering static interface affinity. Furthermore, within-class resilience is governed by epitope architecture: focused antibodies (CC25.56, 6D6, CC25.54) concentrate binding energy into single dominant anchors vulnerable to point mutations, whereas broad antibodies (CC84.2, CC84.24, CC25.4, CC25.43) distribute binding energetics across multi-residue contact networks. These quantitative findings align directly with experimental neutralization data. The structural immutability of the β-sheet-core module provides a mechanistic explanation for why CR3022-site antibodies CC84.2 and CC84.24 retain activity against highly evasive Omicron sublineages BA.2.86 and JN.1. A complete absence of energetic or allosteric hotspots at major Class 1/2 escape loci explains the cross-variant breadth exhibited by both si-lent-face classes. By establishing how silent-face antibodies balance potency, breadth, and resili-ence, this work offers a predictive biophysical framework for tracking viral antigenic drift and designing durable, multi-epitope antibody cocktails.