ArticleProtein science : a publication of the Protein Society2024
Dynamic interchange between two protonation states is characteristic of active sites of cholinesterases.
Article in Protein science : a publication of the Protein Society, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers, 1 of them a synthesis that pooled it.
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Who cites it
7 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Hydrated proton complexes supplementation for tumor microenvironment reprogramming: a bioenergetic strategy targeting the Warburg effect and mitochondrial dysfunction.Frontiers in oncology · 2025Pooled it
- Computational engineering of the polyester hydrolase PHL7 for efficient poly(ethylene terephthalate) degradation in biocatalytic recycling processes.Nature communications · 2026Article
- Ferroptosis-mediated anticancer activity of endoperoxide-containing steroids derived fromAnimal cells and systems · 2026Article
- Acetylcholinesterase: Structure, dynamics, and interactions with organophosphorus compounds.Protein science : a publication of the Protein Society · 2025Review
- Long-Range Electrostatics in Serine Proteases: Machine Learning-Driven Reaction Sampling Yields Insights for Enzyme Design.Journal of chemical information and modeling · 2025Article
- New views on physiological functions and regulation of butyrylcholinesterase and potential therapeutic interventions.Frontiers in molecular biosciences · 2025Review
- Dynamic interchange between two protonation states is characteristic of active sites of cholinesterases.Protein science : a publication of the Protein Society · 2024Article
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Authors and funding
3 authors.
Funding
Abstract
Cholinesterases are well-known and widely studied enzymes crucial to human health and involved in neurology, Alzheimer's, and lipid metabolism. The protonation pattern of active sites of cholinesterases influences all the chemical processes within, including reaction, covalent inhibition by nerve agents, and reactivation. Despite its significance, our comprehension of the fine structure of cholinesterases remains limited. In this study, we employed enhanced-sampling quantum-mechanical/molecular-mechanical calculations to show that cholinesterases predominantly operate as dynamic mixtures of two protonation states. The proton transfer between two non-catalytic glutamate residues follows the Grotthuss mechanism facilitated by a mediator water molecule. We show that this uncovered complexity of active sites presents a challenge for classical molecular dynamics simulations and calls for special treatment. The calculated proton transfer barrier of 1.65 kcal/mol initiates a discussion on the potential existence of two coupled low-barrier hydrogen bonds in the inhibited form of butyrylcholinesterase. These findings expand our understanding of structural features expressed by highly evolved enzymes and guide future advances in cholinesterase-related protein and drug design studies.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.