{"doi":"10.1101/2025.01.13.632878","title":"Interpretable adenylation domain specificity prediction using protein language models","abstract":"Natural products have long been a rich source of diverse and clinically effective drug candidates. Non-ribosomal peptides (NRPs), polyketides (PKs), and NRP-PK hybrids are three classes of natural products that display a broad range of bioactivities, including antibiotic, antifungal, anticancer, and immunosuppressant activities. However, discovering these compounds through traditional bioactivity-guided techniques is costly and time-consuming, often resulting in the rediscovery of known molecules. Consequently, genome mining has emerged as a high-throughput strategy to screen hundreds of thousands of microbial genomes to identify their potential to produce novel natural products. Adenylation domains play a key role in the biosynthesis of NRPs and NRP-PKs by recruiting substrates to incrementally build the final structure. We propose MASPR, a machine learning method that leverages protein language models for accurate and interpretable predictions of A-domain substrate specificities. MASPR demonstrates superior accuracy and generalization over existing methods and is capable of predicting substrates not present in its training data, or zero-shot classification. We use MASPR to develop Seq2Hybrid, an efficient algorithm to predict the structure of hybrid NRP-PK natural products from microbial genomes. Using Seq2Hybrid, we propose putative biosynthetic gene clusters for the orphan natural products Octaminomycin A, Dityromycin, SW-163B, and JBIR-39.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":560551,"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":0.9512,"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":501417,"name":"Andrew T. McNutt","orcid":"0000-0001-6497-6019","position":1,"is_corresponding":false},{"id":18779,"name":"Caleb N. Ellington","orcid":"0000-0001-7029-8023","position":2,"is_corresponding":false},{"id":1462737,"name":"Krish Suraparaju","orcid":null,"position":3,"is_corresponding":false},{"id":1462432,"name":"Nan Fang","orcid":"0000-0003-2346-2438","position":4,"is_corresponding":false},{"id":1236907,"name":"Donghui Yan","orcid":"0000-0002-5131-1509","position":5,"is_corresponding":false},{"id":1046757,"name":"Benjamin Krummenacher","orcid":null,"position":6,"is_corresponding":false},{"id":1462433,"name":"Sitong Li","orcid":"0000-0002-7531-400X","position":7,"is_corresponding":false},{"id":1462738,"name":"Camilla Bodden","orcid":null,"position":8,"is_corresponding":false},{"id":18781,"name":"Eric P. Xing","orcid":"0009-0005-9158-4201","position":9,"is_corresponding":false},{"id":106872,"name":"Bahar Behsaz","orcid":null,"position":10,"is_corresponding":false},{"id":36750,"name":"David Ryan Koes","orcid":"0000-0002-6892-6614","position":11,"is_corresponding":false},{"id":105875,"name":"Hosein Mohimani","orcid":"0000-0003-3980-2505","position":12,"is_corresponding":false},{"id":28889,"name":"Abhinav Adduri","orcid":"0000-0002-7676-8994","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:42.883572Z","pmid":"39868251","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":[]}