Origins of Enzyme Catalysis: Experimental Findings for C–H Activation, New Models, and Their Relevance to Prevailing Theoretical Constructs

The physical basis for enzymatic rate accelerations is a subject of great fundamental interest and of direct relevance to areas that include the de novo design of green catalysts and the pursuit of new drug regimens. Extensive investigations of C–H activating systems have provided considerable insight into the relationship between an enzyme’s overall structure and the catalytic chemistry at its active site. This Perspective highlights recent experimental data for two members of distinct, yet iconic C–H activation enzyme classes, lipoxygenases and prokaryotic alcohol dehydrogenases. The data necessitate a reformulation of the dominant textbook definition of biological catalysis. A multidimensional model emerges that incorporates a range of protein motions that can be parsed into a combination of global stochastic conformational thermal fluctuations and local donor–acceptor distance sampling. These motions are needed to achieve a high degree of precision with regard to internuclear distances, geometries, an...