Issue 28, 2016

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

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

Supplementary files

Article information

Article type
Paper
Submitted
26 May 2016
Accepted
20 Jun 2016
First published
24 Jun 2016

Phys. Chem. Chem. Phys., 2016,18, 19386-19396

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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