title: Evolutionarily conserved linkage between enzyme fold, flexibility, and catalysis.
abstract: Proteins are intrinsically flexible molecules. The role of internal motions in a protein's designated function is widely debated. The role of protein structure in enzyme catalysis is well established, and conservation of structural features provides vital clues to their role in function. Recently, it has been proposed that the protein function may involve multiple conformations: the observed deviations are not random thermodynamic fluctuations; rather, flexibility may be closely linked to protein function, including enzyme catalysis. We hypothesize that the argument of conservation of important structural features can also be extended to identification of protein flexibility in interconnection with enzyme function. Three classes of enzymes (prolyl-peptidyl isomerase, oxidoreductase, and nuclease) that catalyze diverse chemical reactions have been examined using detailed computational modeling. For each class, the identification and characterization of the internal protein motions coupled to the chemical step in enzyme mechanisms in multiple species show identical enzyme conformational fluctuations. In addition to the active-site residues, motions of protein surface loop regions (>10 Å away) are observed to be identical across species, and networks of conserved interactions/residues connect these highly flexible surface regions to the active-site residues that make direct contact with substrates. More interestingly, examination of reaction-coupled motions in non-homologous enzyme systems (with no structural or sequence similarity) that catalyze the same biochemical reaction shows motions that induce remarkably similar changes in the enzyme-substrate interactions during catalysis. The results indicate that the reaction-coupled flexibility is a conserved aspect of the enzyme molecular architecture. Protein motions in distal areas of homologous and non-homologous enzyme systems mediate similar changes in the active-site enzyme-substrate interactions, thereby impacting the mechanism of catalyzed chemistry. These results have implications for understanding the mechanism of allostery, and for protein engineering and drug design.
authors.affiliation: Joint CMU-Pitt Program in Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Arvind
authors.initials: A
authors.lastname: Ramanathan
authors.forename: Pratul K
authors.initials: PK
authors.lastname: Agarwal
mesh_terms: D002384:Catalysis; D003198:Computer Simulation; D021983:Cyclophilins; D004798:Enzymes / Q000737:chemistry* / Q000378:metabolism*; D019143:Evolution, Molecular; D006801:Humans; D008958:Models, Molecular; D010088:Oxidoreductases / Q000737:chemistry / Q000378:metabolism; D019696:Peptidylprolyl Isomerase / Q000737:chemistry / Q000378:metabolism; D017510:Protein Folding; D012260:Ribonucleases / Q000737:chemistry / Q000378:metabolism
chemical_list: D004798:Enzymes; D010088:Oxidoreductases; D012260:Ribonucleases; D021983:Cyclophilins; D019696:Peptidylprolyl Isomerase
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