{"doi":"10.1101/2025.05.19.654863","title":"Decoding protein-peptide interactions using a large, target-agnostic yeast surface display library","abstract":"Protein-peptide interactions underlie key biological processes and are commonly utilized in biomedical research and therapeutic discovery. It is often desirable to identify peptide sequence properties that confer high-affinity binding to a target protein. However, common approaches to such characterization are typically low throughput and only sample regions of sequence space near an initial hit. To overcome these challenges, we built a yeast surface displayed library representing ∼6.1 × 109 unique peptides. We then performed screens against diverse protein targets, including two antibodies, an E3 ubiquitin ligase, and an essential membrane-bound bacterial enzyme. In each case, we observed motifs that appear to drive peptide binding and we identified multiple novel, high-affinity clones. These results highlight the library’s utility as a robust and versatile tool for discovering peptide ligands and for characterizing protein-peptide binding interactions more generally. To enable further studies, we will make the library freely available upon request.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":566673,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9532,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":988321,"name":"Irina Shlosman","orcid":"0000-0002-5672-0942","position":1,"is_corresponding":false},{"id":1326185,"name":"Megha Lakshminarayan","orcid":null,"position":2,"is_corresponding":false},{"id":1470698,"name":"Ziyuan Zhao","orcid":"0000-0002-4403-825X","position":3,"is_corresponding":false},{"id":1186510,"name":"Yue Hong","orcid":"0000-0002-7461-6970","position":4,"is_corresponding":false},{"id":262828,"name":"Radosław P. Nowak","orcid":"0000-0002-0605-0071","position":5,"is_corresponding":false},{"id":262829,"name":"Eric S. Fischer","orcid":"0000-0001-7337-6306","position":6,"is_corresponding":false},{"id":239851,"name":"Andrew C. Kruse","orcid":"0000-0002-1467-1222","position":7,"is_corresponding":false},{"id":859213,"name":"Joseph D. Hurley","orcid":"0000-0002-3903-318X","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-19T02:56:40.491968Z","pmid":"40475574","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}