{"doi":"10.1002/ange.202210254","title":"Molecular Dynamics Simulations Guide Chimeragenesis and Engineered Control of Chemoselectivity in Diketopiperazine Dimerases","abstract":"Abstract In the biosynthesis of the tryptophan‐linked dimeric diketopiperazines (DKPs), cytochromes P450 selectively couple DKP monomers to generate a variety of intricate and isomeric frameworks. To determine the molecular basis for selectivity of these biocatalysts we obtained a high‐resolution crystal structure of selective Csp 2 −N bond forming dimerase, AspB. Overlay of the AspB structure onto C−C and C−N bond forming homolog NzeB revealed no significant structural variance to explain their divergent chemoselectivities. Molecular dynamics (MD) simulations identified a region of NzeB with increased conformational flexibility relative to AspB, and interchange of this region along with a single active site mutation led to a variant that catalyzes exclusive C−N bond formation. MD simulations also suggest that intermolecular C−C or C−N bond formation results from a change in mechanism, supported experimentally through use of a substrate mimic.","journal":"Angewandte Chemie","year":2023,"id":374040,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9475,"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":1056094,"name":"Natalia R. Harris","orcid":"0000-0001-7583-7065","position":1,"is_corresponding":false},{"id":771782,"name":"Jacob N. Sanders","orcid":"0000-0002-2196-4234","position":2,"is_corresponding":false},{"id":311100,"name":"Sean A. Newmister","orcid":"0000-0002-9623-7779","position":3,"is_corresponding":false},{"id":484984,"name":"Yogan Khatri","orcid":"0000-0002-2432-7679","position":4,"is_corresponding":false},{"id":578262,"name":"Mohammad Movassaghi","orcid":"0000-0003-3080-1063","position":5,"is_corresponding":false},{"id":292448,"name":"K. N. Houk","orcid":"0000-0002-8387-5261","position":6,"is_corresponding":false},{"id":311103,"name":"David H. Sherman","orcid":"0000-0001-8334-3647","position":7,"is_corresponding":false},{"id":829540,"name":"Vikram V. Shende","orcid":"0000-0001-8396-6297","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T01:16:11.341687Z","pmid":null,"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":[]}