Temperature affects the catalytic rates of all enzymes. However, the impact of temperature on an enzyme's catalytic activity is convoluted from protein sequence, structure, and dynamics contributions. Understanding and designing the molecular features of enzymes that tune catalytic rates at different temperatures remains a fundamental challenge in biophysics. We employ molecular simulations and mutagenesis experiments to reveal a temperature tuning mechanism of mesophilic and thermophilic homologs of the C domain of bacterial Enzyme l. We find that enzymes can be tuned to their physiological temperatures through a network of frustrated and temerature-sensitive contacts localized in the disordered loops. Furthermore, we find that some exhibit linear and non-linear temperature dependence among temperature-sensitive contacts. These clues offer a promising physics-based approach for tuning enzyme activity.

Mechanism based on energetic frustration governs the activity of mesophilic and thermophilic enzymes

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