Dynamical origins of heat capacity changes in enzyme catalysed reactions

Abstract

Heat capacity changes are emerging as essential for explaining the temperature dependence of enzyme-catalyzed 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 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, but crucially, changes in energetic fluctuations are evident across the whole enzyme including important contributions from oligomeric neighbors and domains distal to the active site. This has general implications for understanding enzyme catalysis, demonstrating a direct connection between functionally important microscopic dynamics and macroscopically measurable quantities.