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Evolution of dynamical networks enhances catalysis in a designer enzyme

Activation heat capacity is emerging as a crucial factor in enzyme thermoadaptation, as shown by the non-Arrhenius behaviour of many natural enzymes. However, its physical origin and relationship to the evolution of catalytic activity remain uncertain. Here we show that directed evolution of a compu...

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Published in:Nature chemistry 2021-10, Vol.13 (10), p.1017-1022
Main Authors: Bunzel, H. Adrian, Anderson, J. L. Ross, Hilvert, Donald, Arcus, Vickery L., van der Kamp, Marc W., Mulholland, Adrian J.
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description Activation heat capacity is emerging as a crucial factor in enzyme thermoadaptation, as shown by the non-Arrhenius behaviour of many natural enzymes. However, its physical origin and relationship to the evolution of catalytic activity remain uncertain. Here we show that directed evolution of a computationally designed Kemp eliminase reshapes protein dynamics, which gives rise to an activation heat capacity absent in the original design. These changes buttress transition-state stabilization. Extensive molecular dynamics simulations show that evolution results in the closure of solvent-exposed loops and a better packing of the active site. Remarkably, this gives rise to a correlated dynamical network that involves the transition state and large parts of the protein. This network tightens the transition-state ensemble, which induces a negative activation heat capacity and non-linearity in the activity–temperature dependence. Our results have implications for understanding enzyme evolution and suggest that selectively targeting the conformational dynamics of the transition-state ensemble by design and evolution will expedite the creation of novel enzymes. Computationally designed enzymes can be substantially improved by directed evolution. Now, it has been shown that evolution can introduce a dynamic network that selectively tightens the transition-state ensemble, giving rise to a negative activation heat capacity. Targeting such transition state conformational dynamics may expedite de novo enzyme creation.
doi_str_mv 10.1038/s41557-021-00763-6
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subjects 631/45/607
639/638/563/606
639/638/77/603
639/638/92/609
Analytical Chemistry
Biochemistry
Buttresses
Catalysis
Catalytic activity
Chemistry
Chemistry and Materials Science
Chemistry/Food Science
Design
Directed evolution
Enzymes
Enzymes - chemistry
Enzymes - metabolism
Evolution
Evolution, Chemical
Heat
Inorganic Chemistry
Molecular dynamics
Molecular Dynamics Simulation
Organic Chemistry
Physical Chemistry
Protein Conformation
Proteins
Specific heat
Temperature dependence
Thermodynamics
title Evolution of dynamical networks enhances catalysis in a designer enzyme
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