ArticleJournal of the American Chemical Society2007
Molecular dynamics simulations of the catalytic pathway of a cysteine protease: a combined QM/MM study of human cathepsin K.
Article in Journal of the American Chemical Society, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 95 citations in OpenAlex.
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- QM/MM Simulations of Afatinib-EGFR Addition: The Role of β-Dimethylaminomethyl Substitution.Journal of chemical theory and computation · 2024Article
- Catalytic Effects of Active Site Conformational Change in the Allosteric Activation of Imidazole Glycerol Phosphate Synthase.ACS catalysis · 2023Article
- Unraveling the catalytic mechanism of SARS-CoV-2 papain-like protease with allosteric modulation of C270 mutation using multiscale computational approaches.Chemical science · 2023Article
- Structural Dynamics of Lys11-Selective Deubiquitinylase Cezanne-1 during the Catalytic Cycle.Journal of chemical information and modeling · 2023Article
- New insights into the catalytic mechanism of the SARS-CoV-2 main protease: an ONIOM QM/MM approach.Molecular diversity · 2022Article
- Covalent Proximity Scanning of a Distal Cysteine to Target PI3Kα.Journal of the American Chemical Society · 2022Article
- Mechanisms of Proteolytic Enzymes and Their Inhibition in QM/MM Studies.International journal of molecular sciences · 2021Review
- An automated protocol for modelling peptide substrates to proteases.BMC bioinformatics · 2020Article
- On the Catalytic Activity of the Engineered Coiled-Coil Heptamer Mimicking the Hydrolase Enzymes: Insights from a Computational Study.International journal of molecular sciences · 2020Article
- Revealing the molecular mechanisms of proteolysis of SARS-CoV-2 MChemical science · 2020Article
- Artificial cysteine-lipases with high activity and altered catalytic mechanism created by laboratory evolution.Nature communications · 2019Article
- Cathepsin L Inhibitors with Activity against the Liver Fluke Identified From a Focus Library of Quinoxaline 1,4-di-Molecules (Basel, Switzerland) · 2019Article
- Comment on "Substrate Folding Modes in Trichodiene Synthase: A Determinant of Chemo- and Stereoselectivity".ACS catalysis · 2018Article
- Can Relative Binding Free Energy Predict Selectivity of Reversible Covalent Inhibitors?Journal of the American Chemical Society · 2017Article
- Distinct Roles of Catalytic Cysteine and Histidine in the Protease and Ligase Mechanisms of Human Legumain As Revealed by DFT-Based QM/MM Simulations.ACS catalysis · 2017Article
- Effects of Glycosylation on the Enzymatic Activity and Mechanisms of Proteases.International journal of molecular sciences · 2016Review
- Insights into the Interactions of Fasciola hepatica Cathepsin L3 with a Substrate and Potential Novel Inhibitors through In Silico Approaches.PLoS neglected tropical diseases · 2015Article
- Predicting the reactivity of nitrile-carrying compounds with cysteine: a combined computational and experimental study.ACS medicinal chemistry letters · 2014Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Molecular dynamics simulations using a combined QM/MM potential have been performed to study the catalytic mechanism of human cathepsin K, a member of the papain family of cysteine proteases. We have determined the two-dimensional free energy surfaces of both acylation and deacylation steps to characterize the reaction mechanism. These free energy profiles show that the acylation step is rate limiting with a barrier height of 19.8 kcal/mol in human cathepsin K and of 29.3 kcal/mol in aqueous solution. The free energy of activation for the deacylation step is 16.7 kcal/mol in cathepsin K and 17.8 kcal/mol in aqueous solution. The reduction of free energy barrier is achieved by stabilization of the oxyanion in the transition state. Interestingly, although the "oxyanion hole" has been formed in the Michaelis complex, the amide units do not donate hydrogen bonds directly to the carbonyl oxygen of the substrate, but they stabilize the thiolate anion nucleophile. Hydrogen-bonding interactions are induced as the substrate amide group approaches the nucleophile, moving more than 2 A and placing the oxyanion in contact with Gln19 and the backbone amide of Cys25. The hydrolysis of peptide substrate shares a common mechanism both for the catalyzed reaction in human cathepsin K and for the uncatalyzed reaction in water. Overall, the nucleophilic attack by Cys25 thiolate and the proton-transfer reaction from His162 to the amide nitrogen are highly coupled, whereas a tetrahedral intermediate is formed along the nucleophilic reaction pathway.
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