{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T02:18:14Z","timestamp":1778552294201,"version":"3.51.4"},"posted":{"date-parts":[[2026,4,30]]},"group-title":"Bioinformatics","reference-count":57,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["1R01HL176858"],"award-info":[{"award-number":["1R01HL176858"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["1R35HL171346"],"award-info":[{"award-number":["1R35HL171346"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>Sequence-based protein\u2013protein interaction (PPI) site predictors typically analyze proteins in isolation, neglecting partner-specific context that is critical for interface specificity, particularly in transient and disordered interactions.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We introduce SPPIDER-seq, a partner-aware PPI site prediction framework that combines pretrained ESM-2 embeddings with a cross-attention architecture to enable residue-level conditioning on interacting partners. We curated non-redundant protein\u2013peptide interaction datasets from BioLiP and used them to train and benchmark two complementary models: a receptor-centric model optimized for structured interfaces and a peptide-centric model tailored to disordered, motif-driven binding. On blind benchmarks, SPPIDER-seq achieved AUROC values up to 0.797 and MCC values up to 0.269, outperforming AlphaFold3 on peptide-mediated and disordered interfaces while remaining complementary on globular complexes. Application to 341 TP53 interaction partners revealed coherent, partner-specific interface patterns across both structured and intrinsically disordered regions.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Availability and Implementation<\/jats:title>\n                  <jats:p>\n                    SPPIDER-seq models, datasets, and the Python code are freely available on the web at:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/github.com\/aporollo-lab\/SPPIDER-seq\">https:\/\/github.com\/aporollo-lab\/SPPIDER-seq<\/jats:ext-link>\n                    and archived on Zenodo at DOI: 10.5281\/zenodo.19835990, corresponding to GitHub release v2.0-manuscript.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Contact<\/jats:title>\n                  <jats:p>\n                    Dr. Aleksey Porollo \u2013\n                    <jats:email>porollay@ucmail.uc.edu<\/jats:email>\n                  <\/jats:p>\n                  <jats:p>\n                    Dr. Jichao Chen \u2013\n                    <jats:email>jichao.chen@cchmc.org<\/jats:email>\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Supplementary Information<\/jats:title>\n                  <jats:p>Available online with the manuscript.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.28.721359","type":"posted-content","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T05:40:16Z","timestamp":1777614016000},"source":"Crossref","is-referenced-by-count":0,"title":["SPPIDER-seq: Sequence-based partner-aware predictor of protein-protein interaction sites"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3202-5099","authenticated-orcid":false,"given":"Aleksey","family":"Porollo","sequence":"first","affiliation":[{"name":"Department of Biostatistics, Health Informatics and Data Sciences, the University of Cincinnati College of Medicine, Cincinnati, OH, USA 45267"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6937-8465","authenticated-orcid":false,"given":"Om","family":"Jadhav","sequence":"additional","affiliation":[{"name":"Department of Computer Science, the University of Cincinnati College of Engineering and Applied Science, Cincinnati, OH, USA 45221"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9036-9847","authenticated-orcid":false,"given":"Aaron","family":"Alvarez","sequence":"additional","affiliation":[{"name":"Department of Computer Science, the University of Cincinnati College of Engineering and Applied Science, Cincinnati, OH, USA 45221"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2749-8550","authenticated-orcid":false,"given":"Jichao","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Biology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH, USA 45229"},{"name":"Department of Pediatrics, the University of Cincinnati College of Medicine, Cincinnati, OH, USA 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