Protein Flexibility and Energy Flow During Enzyme Catalysis

Abstract

Enzymes are dynamic molecules. Although in the past enzymes were viewed as static entities, recent evidence from experimental, theoretical and computational work indicates that protein dynamics play a significant role in enhancing catalytic activity. Investigations of the free energy profile for several proteins such as cyclophilin A and dihydrofolate reductase have revealed a network of protein motions that promote catalytic activity. Results indicate that these reaction-promoting motions are conserved as part of the enzyme fold across several species, even though they have low sequence similarity. Extending our study to a superfamily of enzymes, namely the dinucleotide binding Rossmann Fold proteins (DBRP), shows that in spite of having very low sequence homology and different structural features, the overall intrinsic dynamical flexibility of the superfamily is remarkably well preserved with respect to the catalytic step. The conformational coupling observed between exterior surface regions with the active site entails energetic coupling between them. To characterize this energetic coupling, we use an integrated information theoretic and biophysical approach to analyze residues that may constitute pathways through which energy may propagate from the flexible exterior surface regions to the active site of the protein. Our results reveal significant similarities in the energy flow pathways within the DBRP super-family. This study provides specific insights into how the DBRP super-family of proteins has evolved to catalyze hydride transfer reactions.