Origin of the activity drop with the E50D variant of catalytic antibody 34E4 for Kemp elimination.

The Journal of Physical Chemistry. B
Anastassia N Alexandrova, William L Jorgensen

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 Trp9...Continue Reading

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Sep 5, 2009·Accounts of Chemical Research·Orlando Acevedo, William L Jorgensen
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Sep 7, 2018·Journal of Chemical Theory and Computation·Tamara Husch, Markus Reiher

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