Kinetic View of Enzyme Catalysis from Enhanced Sampling QM/MM Simulations

Abstract

The rate constants of enzyme-catalyzed reactions (k cat ) are often approximated from the barrier height of the reactive step. We introduce an enhanced sampling QM/MM approach that directly calculates the kinetics of enzymatic reactions, without introducing the transition-state theory assumptions, and takes into account the dynamical equilibrium between the reactive and nonreactive conformations of the enzyme/substrate complex. Our computed k cat values are in order-of-magnitude agreement with the experimental data for two representative enzymatic reactions.

Revisiting the reaction pathways for phospholipid hydrolysis catalyzed by phospholipase A2 with QM/MM methods

“…If one considers that the k cat also reflects the free energy associated with the accessibility of catalytically productive conformations, then the relative populations of each reactant state calculated with MD can be incorporated into the estimate of the reaction rate. 84 This assumes that the sampling obtained with MD is statistically representative and that the difference between free energy barriers calculated with QM/MM MD is relatively close to the ideal value. Our estimate with this approach reveals that the assisting-water pathway is about 500 times slower due to the higher free energy barrier and lower abundance of reactive conformations.…”