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Publication - Professor Adrian Mulholland

    Emergence of a Negative Activation Heat Capacity during Evolution of a Designed Enzyme


    Bunzel, A, Kries, H, Marchetti, L, Zeymer, C, Mittl, PRE, Mulholland, A & Hilvert, D, 2019, ‘Emergence of a Negative Activation Heat Capacity during Evolution of a Designed Enzyme’. Journal of the American Chemical Society, vol 141., pp. 11745-11748


    Temperature influences the reaction kinetics and evolvability of all enzymes. To understand how evolution shapes the thermodynamic drivers of catalysis, we optimized the modest activity of a computationally designed enzyme for an elementary proton-transfer reaction by nearly 4 orders of magnitude over 9 rounds of mutagenesis and screening. As theorized for primordial enzymes, the catalytic effects of the original design were almost entirely enthalpic in origin, as were the rate enhancements achieved by laboratory evolution. However, the large reductions in ΔH⧧ were partially offset by a decrease in TΔS⧧ and unexpectedly accompanied by a negative activation heat capacity, signaling strong adaptation to the operating temperature. These findings echo reports of temperature-dependent activation parameters for highly evolved natural enzymes and are relevant to explanations of enzymatic catalysis and adaptation to changing thermal environments.

    Full details in the University publications repository