{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T17:02:06Z","timestamp":1772557326386,"version":"3.50.1"},"reference-count":74,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>The SARS-CoV-2 Omicron variant and its descendants accumulated unprecedented numbers of spike substitutions yet remained transmissible, implying compensatory mechanisms that preserve entry while eroding humoral immunity. We analyzed 32 variants for sequence-level mutation, physicochemical profiling, and epitope disruption; 25 had growth-advantage estimates, and 18 underwent molecular dynamics\/MM-PBSA simulations. We applied a systems-virology framework to the SARS-CoV-2 receptor-binding domain (RBD), integrating immunodominance-weighted epitope conservation (567 B-cell and 97 T-cell epitopes) across variants (Wuhan-Hu-1 to KP.3) with molecular dynamics, molecular mechanics Poisson\u2013Boltzmann surface area (MM-PBSA) binding energetics, and deep mutational scanning (DMS) benchmarking. B-cell epitope conservation declined from a median of 72.7% in pre-Omicron variants to 28.8% in BA.1 and 10.6% in KP.3, and was strongly inversely associated with a breakthrough-infection proxy (Spearman \u03c1 = \u22120.8246, p &lt; 0.001), whereas RBD T-cell epitopes remained comparatively conserved (91.5% to 87.2%). Despite the loss of the ancestral K417\u2013ACE2 D30 salt bridge, Omicron reconfigured the interface via alternative electrostatic contacts (Q493R\u2013E35 and Q498R\u2013D38), producing compensatory interactions captured by MM-PBSA, but with only modest agreement with DMS affinity changes (r = 0.682, p = 0.007), consistent with enthalpy\u2013entropy compensation. Finally, mutation tolerance shifted toward stronger epistatic buffering in Omicron (two-fold higher epistasis than pre-Omicron; p = 0.0093), enabling extensive antigenic change without structural collapse. Together, these results support a multi-objective evolutionary strategy\u2014epitope erosion, interface rewiring, and epistatic compensation\u2014that can be operationalized to prioritize emerging lineages for surveillance and to inform vaccine designs that emphasize conserved T-cell targets.<\/jats:p>","DOI":"10.3390\/pathogens15030272","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T15:15:29Z","timestamp":1772550929000},"page":"272","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond the Mutation Abyss: Revisiting SARS-CoV-2 Receptor-Binding Domain Evolution from ACE2 Binding Optimization to Immune Epitope Remodeling"],"prefix":"10.3390","volume":"15","author":[{"given":"Omar A.","family":"Soliman","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy, University Main Teaching Hospital, Alexandria 21526, Egypt"},{"name":"Human Genetics Department, Medical Research Institute, Alexandria University, Alexandria 21521, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasmine","family":"Shahine","sequence":"additional","affiliation":[{"name":"Microbiology and Immunology Department, Faculty of Pharmacy and Drug Manufacturing, Pharos University in Alexandria, Canal El Mahmoudia Street, Beside Green Plaza Complex, Alexandria 21648, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1963-9838","authenticated-orcid":false,"given":"Daniel","family":"Baecker","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Freie Universit\u00e4t Berlin, K\u00f6nigin-Luise-Stra\u00dfe 2+4, 14195 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed Noby","family":"Amer","sequence":"additional","affiliation":[{"name":"Microbiology and Immunology Department, Faculty of Pharmacy and Drug Manufacturing, Pharos University in Alexandria, Canal El Mahmoudia Street, Beside Green Plaza Complex, Alexandria 21648, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e0160124","DOI":"10.1128\/jvi.01601-24","article-title":"Pathogen genomic surveillance and the AI revolution","volume":"99","author":"Lytras","year":"2025","journal-title":"J. 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