ArticleThe journal of physical chemistry. B2009
Origin of the activity drop with the E50D variant of catalytic antibody 34E4 for Kemp elimination.
Article in The journal of physical chemistry. B, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Semiempirical Quantum-Chemical Methods with Orthogonalization and Dispersion Corrections.Journal of chemical theory and computation · 2019Article
- Exploring the Development of Ground-State Destabilization and Transition-State Stabilization in Two Directed Evolution Paths of Kemp Eliminases.ACS catalysis · 2017Article
- Semiempirical Quantum-Chemical Orthogonalization-Corrected Methods: Benchmarks for Ground-State Properties.Journal of chemical theory and computation · 2016Article
- Computational strategies for the design of new enzymatic functions.Archives of biochemistry and biophysics · 2015Review
- Quantum and Molecular Mechanical (QM/MM) Monte Carlo Techniques for Modeling Condensed-Phase Reactions.Wiley interdisciplinary reviews. Computational molecular science · 2014Article
- Computer aided enzyme design and catalytic concepts.Current opinion in chemical biology · 2014Review
- Engineering a model protein cavity to catalyze the Kemp elimination.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- Challenges and advances in validating enzyme design proposals: the case of kemp eliminase catalysis.Biochemistry · 2011Article
- Advances in quantum and molecular mechanical (QM/MM) simulations for organic and enzymatic reactions.Accounts of chemical research · 2010Article
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Authors and funding
2 authors.
Funding
Abstract
In enzymes, multiple structural effects cooperatively lead to the high catalytic activity, while individually these effects can be small. The design of artificial enzymes requires the understanding and ability to manipulate such subtle effects. The 34E4 catalytic antibody, catalyzing Kemp elimination of 5-nitrobenzisoxazole, and its Glu50Asp (E50D) variant are the subject of the present investigation. This removal of only a methylene group yields an approximately 30-fold reduction in the rate for the catalyzed Kemp elimination. Here, the aim is to understand this difference in the catalytic performance. The mechanism of Kemp elimination catalyzed by 34E4 and the E50D mutant is elucidated using QM/MM Monte Carlo simulations and free energy perturbation theory. In both proteins, the reaction is shown to follow a single-step, concerted mechanism. In the mutant, the activation barrier rises by 2.4 kcal/mol, which corresponds to a 62-fold rate deceleration, which is in good agreement with the experimental data. The positions and functionality of the residues in the active site are monitored throughout the reaction. It is concluded that the looser contact with the base, shorter base-Asn58 contact, less favorable pi-stacking with Trp91 in the transition state of the reaction, and different solvation pattern all contribute to the reduction of the reaction rate in the E50D variant of 34E4.
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