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- W2726292843 endingPage "7041" @default.
- W2726292843 startingPage "7027" @default.
- W2726292843 abstract "Enzymes are widely used in nonaqueous solvents to catalyze non-natural reactions. While experimental measurements showed that the solvent nature has a strong effect on the reaction kinetics, the molecular details of the catalytic mechanism in nonaqueous solvents have remained largely elusive. Here we study the transesterification reaction catalyzed by the paradigm subtilisin Carlsberg serine protease in an organic apolar solvent. The rate-limiting acylation step involves a proton transfer between active-site residues and the nucleophilic attack of the substrate to form a tetrahedral intermediate. We design the first coupled valence-bond state model that simultaneously describes both reactions in the enzymatic active site. We develop a new systematic procedure to parametrize this model on high-level ab initio QM/MM free energy calculations that account for the molecular details of the active site and for both substrate and protein conformational fluctuations. Our calculations show that the reaction energy barrier changes dramatically with the solvent and protein conformational fluctuations. We find that the mechanism of the tetrahedral intermediate formation during the acylation step is similar to that determined under aqueous conditions, and that the proton transfer and nucleophilic attack reactions occur concertedly. We identify the reaction coordinate to be mostly due to the rearrangement of some residual water molecules close to the active site." @default.
- W2726292843 created "2017-07-14" @default.
- W2726292843 creator A5000242134 @default.
- W2726292843 creator A5034203538 @default.
- W2726292843 creator A5042246786 @default.
- W2726292843 creator A5044955290 @default.
- W2726292843 creator A5052991915 @default.
- W2726292843 creator A5064648161 @default.
- W2726292843 creator A5068981113 @default.
- W2726292843 date "2017-07-17" @default.
- W2726292843 modified "2023-10-14" @default.
- W2726292843 title "Coupled Valence-Bond State Molecular Dynamics Description of an Enzyme-Catalyzed Reaction in a Non-Aqueous Organic Solvent" @default.
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