{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T03:28:31Z","timestamp":1792726111808,"version":"4.5.0"},"posted":{"date-parts":[[2025,10,27]]},"group-title":"Bioinformatics","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:00:00Z","timestamp":1761523200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Understanding how viral proteins adapt under immune pressure while preserving viability is crucial for anticipating antibody-resistant variants. We present a probabilistic framework that predicts viral escape trajectories and shows that immune evasion is channeled into a small set of viable \u201cescape funnels\u201d within the vast mutational space. These escape funnels arise from the combined constraints of protein viability and antibody escape, modeled using a generative model trained on homologs and deep mutational scanning data. We derive a mean-field approximation of evolutionary path ensembles, enabling us to quantify both the fitness and entropy of escape routes. Applied to SARS-CoV-2 receptor binding domain, our framework reveals convergent evolution patterns, predicts mutation sites in variants of concern, and explains differences in antibody-cocktail effectiveness. In particular, cocktails with de-correlated escape profiles slow viral adaptation by forcing longer, higher-cost escape paths.<\/jats:p>\n                <jats:sec>\n                  <jats:title>SIGNIFICANCE<\/jats:title>\n                  <jats:p>Viruses evolve to evade our immune defenses, but with constraints. Like navigating a minefield, each step toward immune escape comes at the potential cost of structural stability and functionality. We show that despite the vast mutational space, immune escape is funneled into a small set of predictable pathways. Using a statistical-physics model grounded in antibody experiments and SARS-CoV-2 epidemiology data, we identify these escape funnels\u2014enabling therapies designed to block them before they are ever used.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.26.684604","type":"posted-content","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T03:20:10Z","timestamp":1761621610000},"source":"Crossref","is-referenced-by-count":4,"title":["Constrained Evolutionary Funnels Shape Viral Immune Escape"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2359-5185","authenticated-orcid":false,"given":"Marian","family":"Huot","sequence":"first","affiliation":[{"name":"Laboratory of Physics of the \u00c9cole Normale Sup\u00e9rieure, CNRS UMR 8023 and PSL Research, Sorbonne Universit\u00e9, 24 rue Lhomond, Paris, France"},{"name":"Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5503-1838","authenticated-orcid":false,"given":"Dianzhuo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA"},{"name":"John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4769-2265","authenticated-orcid":false,"given":"Eugene","family":"Shakhnovich","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4459-0204","authenticated-orcid":false,"given":"R\u00e9mi","family":"Monasson","sequence":"additional","affiliation":[{"name":"Laboratory of Physics of the \u00c9cole Normale Sup\u00e9rieure, CNRS UMR 8023 and PSL Research, Sorbonne Universit\u00e9, 24 rue Lhomond, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1852-7789","authenticated-orcid":false,"given":"Simona","family":"Cocco","sequence":"additional","affiliation":[{"name":"Laboratory of 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