{"doi":"10.1093/nar/gkad260","title":"Catalytic mechanism and pH dependence of a methyltransferase ribozyme (MTR1) from computational enzymology","abstract":"A methyltransferase ribozyme (MTR1) was selected in vitro to catalyze alkyl transfer from exogenous O6-methylguanine (O6mG) to a target adenine N1, and recently, high-resolution crystal structures have become available. We use a combination of classical molecular dynamics, ab initio quantum mechanical/molecular mechanical (QM/MM) and alchemical free energy (AFE) simulations to elucidate the atomic-level solution mechanism of MTR1. Simulations identify an active reactant state involving protonation of C10 that hydrogen bonds with O6mG:N1. The deduced mechanism involves a stepwise mechanism with two transition states corresponding to proton transfer from C10:N3 to O6mG:N1 and rate-controlling methyl transfer (19.4 kcal·mol-1 barrier). AFE simulations predict the pKa for C10 to be 6.3, close to the experimental apparent pKa of 6.2, further implicating it as a critical general acid. The intrinsic rate derived from QM/MM simulations, together with pKa calculations, enables us to predict an activity-pH profile that agrees well with experiment. The insights gained provide further support for a putative RNA world and establish new design principles for RNA-based biochemical tools.","journal":"Nucleic Acids Research","year":2023,"id":329410,"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":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9581,"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":635960,"name":"Şölen Ekesan","orcid":"0000-0002-5598-5754","position":1,"is_corresponding":false},{"id":345742,"name":"Timothy J. Giese","orcid":"0000-0002-0653-9168","position":2,"is_corresponding":false},{"id":1052095,"name":"Timothy J. Wilson","orcid":"0000-0002-3427-593X","position":3,"is_corresponding":false},{"id":1052096,"name":"Jie Deng","orcid":"0000-0003-1606-9259","position":4,"is_corresponding":false},{"id":252275,"name":"Lin Huang","orcid":"0000-0002-2121-365X","position":5,"is_corresponding":false},{"id":252276,"name":"David M.J. Lilley","orcid":"0000-0001-6882-2818","position":6,"is_corresponding":false},{"id":61660,"name":"Darrin M. York","orcid":"0000-0002-9193-7055","position":7,"is_corresponding":false},{"id":553463,"name":"Erika McCarthy","orcid":"0000-0001-8089-0207","position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":null,"created_at":"2026-07-19T01:09:01.509601Z","pmid":"37070188","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":[]}