4.8 Letter

Comment on: Computer Simulations Reveal an Entirely Entropic Activation Barrier for the Chemical Step in a Designer Enzyme

Journal

ACS CATALYSIS
Volume 13, Issue 15, Pages 10527-10530

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acscatal.3c01906

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Activation heat capacity is an important factor in enzyme evolution and thermoadaptation. We found that the emergence of curved activity-temperature profiles in a designer enzyme was due to the selective rigidification of its transition state ensemble that induced an activation heat capacity. However, simulations by angstrom qvist challenged our findings, suggesting that the experimental observations were caused by a change in the rate-limiting step.
Activation heat capacity has been proposed as an important factor in enzyme evolution and thermoadaptation. We previously demonstrated that the emergence of curved activity-temperature profiles during the evolution of a designer enzyme was due to the selective rigidification of its transition state ensemble that induced an activation heat capacity. angstrom qvist challenged our findings with molecular dynamics simulations suggesting that a change in the rate-limiting step underlies the experimental observations. As we describe here, angstrom qvist's model is not consistent with the experimental trends observed for the chemical step of the catalyzed reaction (kcat). We suggest that this discrepancy arises because the simulations performed by angstrom qvist were limited by restraints and short simulation times, which do not allow sampling of the motions responsible for the observed activation heat capacity.

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