Abstract
Heat capacity changes are emerging as essential for explaining the temperature dependence of enzyme-catalysed reaction rates. This has important implications for enzyme kinetics, thermoadaptation and evolution, but the physical basis of these heat capacity changes is unknown. Here we show by a combination of experiment and simulation, for two quite distinct enzymes (dimeric ketosteroid isomerase and monomeric alpha-glucosidase), that the activation heat capacity change for the catalysed reaction can be predicted through atomistic molecular dynamics simulations. The simulations reveal subtle and surprising underlying dynamical changes: tightening of loops around the active site is observed, along with changes in energetic fluctuations across the whole enzyme including important contributions from oligomeric neighbours and domains distal to the active site. This has general implications for understanding enzyme catalysis and demonstrating a direct connection between functionally important microscopic dynamics and macroscopically measurable quantities.
Highlights
Heat capacity changes are emerging as essential for explaining the temperature dependence of enzyme-catalysed reaction rates
We recently developed macromolecular rate theory (MMRT)[6,7], which explains the temperature dependence of enzymes including an intrinsic temperature profile including an optimum temperature (Topt) in the absence of denaturation by introducing the concept of heat capacity changes along the reaction coordinate: the heat capacity (CP) for the enzyme–substrate complex is generally larger than CP for the enzyme–transition state (TS) complex, in enzymes for which the chemical reaction is rate limiting
An ΔCPz values for each enzyme is the position of the optimum temperature (Topt) for activity as these parameters are correlated
Summary
Heat capacity changes are emerging as essential for explaining the temperature dependence of enzyme-catalysed reaction rates. The simulations reveal subtle and surprising underlying dynamical changes: tightening of loops around the active site is observed, along with changes in energetic fluctuations across the whole enzyme including important contributions from oligomeric neighbours and domains distal to the active site This has general implications for understanding enzyme catalysis and demonstrating a direct connection between functionally important microscopic dynamics and macroscopically measurable quantities. Changes in temperature can potentially affect features of the enzymecatalysed reaction outside the chemical steps, such as substrate binding, product release and conformational changes Despite these complexities, enzymes generally show a characteristic temperature profile including an optimum temperature (Topt) for activity above which rates decline with increasing temperature. Been This is observed for proteindirectly analogous to temperature-dependent curvature in protein stability due to ΔCP that gives rise to both high- and low-temperature denaturation[10]
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