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• W2045440995 endingPage "13645" @default.
• W2045440995 startingPage "13633" @default.
• W2045440995 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 Å 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." @default.
• W2045440995 created "2016-06-24" @default.
• W2045440995 creator A5023727290 @default.
• W2045440995 creator A5033170304 @default.
• W2045440995 creator A5051728653 @default.
• W2045440995 date "2007-10-13" @default.
• W2045440995 modified "2023-10-02" @default.
• W2045440995 title "Molecular Dynamics Simulations of the Catalytic Pathway of a Cysteine Protease: A Combined QM/MM Study of Human Cathepsin K" @default.
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• W2045440995 doi "https://doi.org/10.1021/ja074222+" @default.
• W2045440995 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2556303" @default.
• W2045440995 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/17935329" @default.
• W2045440995 hasPublicationYear "2007" @default.
• W2045440995 type Work @default.
• W2045440995 sameAs 2045440995 @default.

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