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Issue 28, 2016
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The role of side chain entropy and mutual information for improving the de novo design of Kemp eliminases KE07 and KE70

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Abstract

Side chain entropy and mutual entropy information between residue pairs have been calculated for two de novo designed Kemp eliminase enzymes, KE07 and KE70, and for their most improved versions at the end of laboratory directed evolution (LDE). We find that entropy, not just enthalpy, helped to destabilize the preference for the reactant state complex of the designed enzyme as well as favoring stabilization of the transition state complex for the best LDE enzymes. Furthermore, residues with the highest side chain couplings as measured by mutual information, when experimentally mutated, were found to diminish or annihilate catalytic activity, some of which were far from the active site. In summary, our findings demonstrate how side chain fluctuations and their coupling can be an important design feature for de novo enzymes, and furthermore could be utilized in the computational steps in lieu of or in addition to the LDE steps in future enzyme design projects.

Graphical abstract: The role of side chain entropy and mutual information for improving the de novo design of Kemp eliminases KE07 and KE70

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Publication details

The article was received on 26 May 2016, accepted on 20 Jun 2016 and first published on 24 Jun 2016


Article type: Paper
DOI: 10.1039/C6CP03622H
Citation: Phys. Chem. Chem. Phys., 2016,18, 19386-19396
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    The role of side chain entropy and mutual information for improving the de novo design of Kemp eliminases KE07 and KE70

    A. Bhowmick, S. C. Sharma, H. Honma and T. Head-Gordon, Phys. Chem. Chem. Phys., 2016, 18, 19386
    DOI: 10.1039/C6CP03622H

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