Dynamical origins of heat capacity changes in enzyme-catalysed reactions

• Published in: Nature communications Vol. 9; no. 1; pp. 1177 - 7
• Main Authors: van der Kamp, Marc W, Prentice, Erica J, Kraakman, Kirsty L, Connolly, Michael, Mulholland, Adrian J, Arcus, Vickery L
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 21.03.2018; Nature Publishing Group UK; Nature Portfolio
• Subjects: 1-Deoxynojirimycin - chemistry; 1-Deoxynojirimycin - metabolism; alpha-Glucosidases - chemistry; alpha-Glucosidases - genetics; alpha-Glucosidases - metabolism; Bacillus subtilis - chemistry; Bacillus subtilis - enzymology; Bacterial Proteins - chemistry; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biocatalysis; Catalysis; Catalytic Domain; Cloning, Molecular; Comamonas testosteroni - chemistry; Comamonas testosteroni - enzymology; Crystallography, X-Ray; Enzyme kinetics; Escherichia coli - genetics; Escherichia coli - metabolism; Gene Expression; Genetic Vectors - chemistry; Genetic Vectors - metabolism; Glucosidase; Heat; Hot Temperature; Ketosteroid isomerase; Kinetics; Molecular dynamics; Molecular Dynamics Simulation; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Protein Multimerization; Reaction kinetics; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Simulation; Specific heat; Steroid Isomerases - chemistry; Steroid Isomerases - genetics; Steroid Isomerases - metabolism; Substrate Specificity; Temperature dependence; Thermodynamics; Variation; α-Glucosidase
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03597-y

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.