title: Preorganization and protein dynamics in enzyme catalysis.
abstract: Recently, an alternative has been offered to the concept of transition state (TS) stabilization as an explanation for rate enhancements in enzyme-catalyzed reactions. Instead, most of the rate increase has been ascribed to preorganization of the enzyme active site to bind substrates in a geometry close to that of the TS, which then transit the activation barrier impelled by motions along the reaction coordinate. The question as to how an enzyme achieves such preorganization and concomitant TS stabilization as well as potential coupled motions along the reaction coordinate leads directly to the role of protein dynamic motion. Dihydrofolate reductase (DHFR) is a paradigm in which the role of dynamics in catalysis continues to be unraveled by a wealth of kinetic, structural, and computational studies. DHFR has flexible loop regions adjacent to the active site whose motions modulate passage through the kinetically preferred pathway. The participation of residues distant from the DHFR active site in enhancing the rate of hydride transfer, however, is unanticipated and may signify the importance of long range protein motions. The general significance of protein dynamics in understanding other biological processes is briefly discussed.
authors.affiliation: Department of Chemistry, Pennsylvania State University, University Park, 16802, USA.
authors.forename: P T Ravi
authors.initials: PT
authors.lastname: Rajagopalan
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Benkovic
mesh_terms: D000429:Alcohol Oxidoreductases / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002384:Catalysis; D004798:Enzymes / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008956:Models, Chemical; D009038:Motion; D011487:Protein Conformation
chemical_list: D004798:Enzymes; D000429:Alcohol Oxidoreductases; C056570:dihydroflavanol 4-reductase