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This homology leads to \u201cdata leakage\u201d in standard random validation splits, yielding inflated performance metrics that fail to translate into real-world biosurveillance utility.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We present Protein Representation Inference for Mutation Evaluation (PRIME), a framework that integrates domain-specific fine-tuning with a rigorous position-stratified validation protocol to evaluate viral threats. Using a dataset of 347,432 SARS-CoV-2 receptor binding domain (RBD) sequences, we demonstrate that while random training data split yields deceptive R\n                      <jats:sup>2<\/jats:sup>\n                      values (&gt;\u20090.90), they fail to generalize to novel mutational sites. By benchmarking models up to 650\u00a0M parameters, we show that domain-specific fine-tuning of the ESM-C 600\u00a0M model with correctly stratified data provides an initial demonstration of predictive signal for binding affinity and expression at unseen mutational sites of binding affinity and expression on unseen sites (R\n                      <jats:sup>2<\/jats:sup>\n                      ~0.23), a significant advancement over base foundation models which exhibit no predictive power (R\n                      <jats:sup>2<\/jats:sup>\n                      &lt;0). PRIME\u2019s embedding-based clustering identified 3.03% of bat coronavirus sequences as candidates for further experimental prioritization based on their functional similarity to human-infective strains in embedding space, offering a perspective complementary to traditional phylogenetic methods.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>PRIME establishes a new benchmark for the application of PLMs in pathogen surveillance. Our findings demonstrate that state-of-the-art models and fine-tuning, when paired with stratified validation, provide biologically meaningful insights into pathogen evolution and zoonotic risk.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12864-026-12976-5","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T23:55:16Z","timestamp":1780098916000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["PRIME: An evaluation framework for protein representation inference and generalization in viral mutation space"],"prefix":"10.1186","volume":"27","author":[{"given":"Kaetlyn","family":"Gibson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po-E","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Dix","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Wei","family":"Hung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George Widgery","family":"Stelle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Babinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Chain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,30]]},"reference":[{"key":"12976_CR1","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1038\/nrg2583","volume":"10","author":"OG Pybus","year":"2009","unstructured":"Pybus OG, Rambaut A. 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