{"doi":"10.1093/nar/gkaa1215","title":"Structural interpretation of the effects of threo-nucleotides on nonenzymatic template-directed polymerization","abstract":"The prebiotic synthesis of ribonucleotides is likely to have been accompanied by the synthesis of noncanonical nucleotides including the threo-nucleotide building blocks of TNA. Here, we examine the ability of activated threo-nucleotides to participate in nonenzymatic template-directed polymerization. We find that primer extension by multiple sequential threo-nucleotide monomers is strongly disfavored relative to ribo-nucleotides. Kinetic, NMR and crystallographic studies suggest that this is due in part to the slow formation of the imidazolium-bridged TNA dinucleotide intermediate in primer extension, and in part because of the greater distance between the attacking RNA primer 3'-hydroxyl and the phosphate of the incoming threo-nucleotide intermediate. Even a single activated threo-nucleotide in the presence of an activated downstream RNA oligonucleotide is added to the primer 10-fold more slowly than an activated ribonucleotide. In contrast, a single activated threo-nucleotide at the end of an RNA primer or in an RNA template results in only a modest decrease in the rate of primer extension, consistent with the minor and local structural distortions revealed by crystal structures. Our results are consistent with a model in which heterogeneous primordial oligonucleotides would, through cycles of replication, have given rise to increasingly homogeneous RNA strands.","journal":"Nucleic Acids Research","year":2020,"id":78385,"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":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9525,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":407630,"name":"Seohyun Chris Kim","orcid":"0000-0002-2230-1774","position":1,"is_corresponding":false},{"id":407631,"name":"Chun Pong Tam","orcid":"0000-0001-6381-9011","position":2,"is_corresponding":false},{"id":408351,"name":"Victor S. Lelyveld","orcid":null,"position":3,"is_corresponding":false},{"id":407632,"name":"Saikat Bala","orcid":"0000-0002-5285-4476","position":4,"is_corresponding":false},{"id":407633,"name":"John C. Chaput","orcid":"0000-0003-1393-135X","position":5,"is_corresponding":false},{"id":366275,"name":"Jack W. Szostak","orcid":"0000-0003-4131-1203","position":6,"is_corresponding":false},{"id":407629,"name":"Wen Zhang","orcid":"0000-0003-4811-4384","position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-18T21:49:40.769098Z","pmid":"33347562","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":[]}