Correlated conformational fluctuations during enzymatic catalysis: Implications for catalytic rate enhancement

Correlated enzymatic conformational fluctuations are shown to contribute to the rate of enhancement achieved during catalysis. Cytidine deaminase serv es as a model system. Crystallographic temperature factor data for this enz yme complexed with substrate analog, transition-state analog, and product a re available, thereby establishing a measure of atomic scale conformational fluctuations along the (approximate) reaction coordinate. First, a neural network-based algorithm is used to visualize the decreased conformational f luctuations at the transition state. Second, a dynamic diffusion equation a long the reaction coordinate is solved and shows that the flux velocity thr ough the associated enzymatic conformation space is greatest at the transit ion state. These results suggest (1) that there are both dynamic and energe tic restrictions to conformational fluctuations at the transition state, (2 ) that enzymatic catalysis occurs on a fluctuating potential energy surface , and (3) a form for the potential energy. The Michaelis-Menten equations a re modified to describe catalysis on this fluctuating potential energy prof ile, leading to enhanced catalytic rates when fluctuations along the reacti on coordinate are appropriately correlated. This represents a dynamic tunin g of the enzyme for maximally effective transformation of the ES complex in to EP.