{"doi":"10.1101/2023.11.01.565201","title":"Small-molecule binding and sensing with a designed protein family","abstract":"Abstract Despite transformative advances in protein design with deep learning, the design of small-molecule–binding proteins and sensors for arbitrary ligands remains a grand challenge. Here we combine deep learning and physics-based methods to generate a family of proteins with diverse and designable pocket geometries, which we employ to computationally design binders for six chemically and structurally distinct small-molecule targets. Biophysical characterization of the designed binders revealed nanomolar to low micromolar binding affinities and atomic-level design accuracy. The bound ligands are exposed at one edge of the binding pocket, enabling the de novo design of chemically induced dimerization (CID) systems; we take advantage of this to create a biosensor with nanomolar sensitivity for cortisol. Our approach provides a general method to design proteins that bind and sense small molecules for a wide range of analytical, environmental, and biomedical applications.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":389484,"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":34,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9505,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":245440,"name":"Samuel J. Pellock","orcid":"0000-0002-7557-7985","position":1,"is_corresponding":false},{"id":552675,"name":"Christoffer Norn","orcid":"0000-0002-1450-4651","position":2,"is_corresponding":false},{"id":552249,"name":"Doug Tischer","orcid":"0000-0003-3633-5542","position":3,"is_corresponding":false},{"id":552413,"name":"Justas Dauparas","orcid":"0000-0002-0030-144X","position":4,"is_corresponding":false},{"id":1160644,"name":"Ivan Anischenko","orcid":null,"position":5,"is_corresponding":false},{"id":805680,"name":"Jaron A. M. Mercer","orcid":"0000-0001-7078-614X","position":6,"is_corresponding":false},{"id":268184,"name":"Alex Kang","orcid":"0000-0001-5487-0499","position":7,"is_corresponding":false},{"id":453451,"name":"Asim K. Bera","orcid":"0000-0001-9473-2912","position":8,"is_corresponding":false},{"id":838655,"name":"Hannah Nguyen","orcid":"0000-0001-9696-4004","position":9,"is_corresponding":false},{"id":218558,"name":"Inna Goreshnik","orcid":"0000-0002-9254-9249","position":10,"is_corresponding":false},{"id":86017,"name":"Dionne Vafeados","orcid":"0000-0002-2560-8907","position":11,"is_corresponding":false},{"id":1160645,"name":"Nicole Roullier","orcid":null,"position":12,"is_corresponding":false},{"id":1159851,"name":"Hannah L. Han","orcid":"0000-0002-4787-5168","position":13,"is_corresponding":false},{"id":218559,"name":"Brian Coventry","orcid":"0000-0002-6910-6255","position":14,"is_corresponding":false},{"id":807771,"name":"Hugh K. Haddox","orcid":"0000-0001-8324-8324","position":15,"is_corresponding":false},{"id":32147,"name":"David R. Liu","orcid":"0000-0002-9943-7557","position":16,"is_corresponding":false},{"id":805631,"name":"Hsien‐Wei Yeh","orcid":"0000-0002-9023-776X","position":17,"is_corresponding":false},{"id":105706,"name":"David Baker","orcid":"0000-0001-7896-6217","position":18,"is_corresponding":false},{"id":614113,"name":"Gyu Rie Lee","orcid":"0000-0002-9119-5303","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T01:18:27.054415Z","pmid":"37961294","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":[]}