Brownian dynamics simulations of the encounter kinetics between the active site of the wild-type and Glu199 mutant of Torpedo californica acetylcholinesterase (TcAChE) with a charged substrate were performed. In addition, ab initio quantum chemical calculations using the 3-21G basis set were undertaken to probe the energetics of the transformation of the Michaelis complex into a covalently bound tetrahedral intermediate using various models of the wild-type and Glu199Gln mutant active sites. The quantum calculations predicted about a factor of 32 reduction in the rate of formation of the tetrahedral intermediate upon the Glu199Gln mutation and showed that the Glu199 residue located in the proximity of the enzyme active triad boosts AChE's activity in a dual fashion: (1) by increasing the encounter rate due to the favorable modification of the electric field inside the enzyme reaction gorge and (2) by stabilization of the transition state for the first chemical step of catalysis. Our calculations also demonstrate the critical role of the oxyanion hole in stabilization of the tetrahedral intermediate and suggests that a charge relay mechanism may operate in the Glu199Gln mutant AChE as opposed to a general base mechanism as in the wild-type enzyme.