{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:40:43Z","timestamp":1785422443427,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,3]]},"group-title":"Biophysics","reference-count":120,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T00:00:00Z","timestamp":1775174400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["1R01AI181600-01"],"award-info":[{"award-number":["1R01AI181600-01"]}],"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"publisher"}]},{"award":["5R01AI181600-02"],"award-info":[{"award-number":["5R01AI181600-02"]}],"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"publisher"}]},{"award":["Subaward 6069-SC24-11"],"award-info":[{"award-number":["Subaward 6069-SC24-11"]}],"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>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\u2014SCORE-A, SCORE-B, and SCORE-C\u2014retains 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\u2014\u201cenergetic playgrounds\u201d that permit mutational exploration without destabilizing the RBD\u2014while 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 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.<\/jats:p>","DOI":"10.64898\/2026.04.02.716254","type":"posted-content","created":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T03:20:12Z","timestamp":1775272812000},"source":"Crossref","is-referenced-by-count":0,"title":["Frustration Landscapes of Broadly Neutralizing SARS-CoV-2 Spike Antibodies Targeting Conserved Epitopes Reveal Energetic Logic of Escape-Proof and Escape-Prone Mechanisms"],"prefix":"10.64898","author":[{"given":"Mohammed","family":"Alshahrani","sequence":"first","affiliation":[{"name":"Keck Center for Science and Engineering, Department of Biological Sciences, Schmid College of Science and Technology, Chapman University, Orange, CA 92866, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Will","family":"Gatlin","sequence":"additional","affiliation":[{"name":"Keck Center for Science and Engineering, Department of Biological Sciences, Schmid College of Science and Technology, Chapman University, Orange, CA 92866, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Ludwick","sequence":"additional","affiliation":[{"name":"Keck Center for Science and Engineering, Department of Biological Sciences, Schmid College of Science and Technology, Chapman University, Orange, CA 92866, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas","family":"Turano","sequence":"additional","affiliation":[{"name":"Keck Center for Science and Engineering, Department of Biological Sciences, Schmid College of Science and Technology, Chapman University, Orange, CA 92866, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Foley","sequence":"additional","affiliation":[{"name":"Keck Center for Science and Engineering, Department of Biological Sciences, Schmid College of Science and Technology, Chapman University, Orange, CA 92866, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4507-4471","authenticated-orcid":false,"given":"Gennady","family":"Verkhivker","sequence":"additional","affiliation":[{"name":"Keck Center for Science and Engineering, Department of Biological Sciences, Schmid College of Science and Technology, Chapman University, Orange, CA 92866, United States of America"},{"name":"Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA 92618, United States of America"},{"name":"Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California 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