{"doi":"10.1101/2025.11.05.686872","title":"Environmental Contributions to Proton Sharing in Protein Low-Barrier Hydrogen Bonds","abstract":"Hydrogen bonds (H-bonds) are central to biomolecular structure and dynamics. Although H-bonds are typically characterized by well-defined proton positions, proton delocalization can play a key role in facilitating enzyme catalysis and allostery in some systems. Experimentally locating protons is difficult, hampering the study of the proton mobility in H-bonds. We used neutron crystallography and large quantum mechanics/molecular mechanics-Born Oppenheimer molecular dynamics (QM/MM-BOMD) simulations of human DJ-1 and its bacterial homolog YajL to validate atomic resolution X-ray crystallographic bond length analysis, directly visualizing the shared deuteron in a low-barrier hydrogen bond (LBHB) between Glu14-Asp23 in YajL that is a conventional H-bond in DJ-1. In addition, X-ray bond length analysis of protiated and perdeuterated DJ-1 and YajL shows no significant effect of deuteron substitution on these carboxylic acid-carboxylate H-bonds but does reveal an effect at the active site glutamic acid. Residues in the vicinity of Glu14-Asp23 that might favor LBHB formation in YajL were interrogated by mutagenesis of homologous residues in DJ-1. X-ray bond length analysis and QM/MM-BOMD simulations demonstrate that a distal I21T DJ-1 substitution increases proton delocalization in the Glu-Asp H-bond. In addition, simulations show that the extent of proton mobility in the H-bond influences correlated dimer-spanning motions in YajL and DJ-1. In total, we show that mutations within extended H-bonding networks can modulate proton transfer barriers in carboxylic acid-carboxylate H-bonds, allowing proton delocalization to be engineered using combined bioinformatic, structural, and computational information.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":580335,"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":0.9594,"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":512423,"name":"Oksana Gerlits","orcid":"0000-0002-0836-826X","position":1,"is_corresponding":false},{"id":226918,"name":"Daniel W. Kneller","orcid":"0000-0002-5416-5789","position":2,"is_corresponding":false},{"id":443196,"name":"Kevin L. Weiss","orcid":"0000-0002-6486-8007","position":3,"is_corresponding":false},{"id":226923,"name":"Leighton Coates","orcid":"0000-0003-2342-049X","position":4,"is_corresponding":false},{"id":397196,"name":"Mark A. Hix","orcid":"0000-0003-3371-0116","position":5,"is_corresponding":false},{"id":1447850,"name":"Solomon Yamoah Effah","orcid":"0000-0003-1342-8148","position":6,"is_corresponding":false},{"id":226924,"name":"Andrey Kovalevsky","orcid":"0000-0003-4459-9142","position":7,"is_corresponding":false},{"id":724809,"name":"Alice R. Walker","orcid":"0000-0002-8617-3425","position":8,"is_corresponding":false},{"id":388663,"name":"Mark A. Wilson","orcid":"0000-0001-6317-900X","position":9,"is_corresponding":false},{"id":1491159,"name":"J H Lin","orcid":"0000-0002-7220-6150","position":0,"is_corresponding":true}],"reference_count":94,"raw_metadata":null,"created_at":"2026-07-19T02:58:38.868285Z","pmid":"41279124","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":[]}