Comparison of formation of reactive conformers for the SN2 displacements by CH3CO2- in water and by Asp124-CO2- in a haloalkane dehalogenase.

The S(N)2 displacement of Cl(-) from 1,2-dichloroethane by acetate (CH(3)CO(2)(-)) in water and by the carboxylate of the active site aspartate in the haloalkane dehalogenase of Xanthobacter autothropicus have been compared by using molecular dynamics simulations. In aqueous solution, six families of contact-pair structures (I-VI) were identified, and their relative concentrations and dissociation rate constants were determined. The near attack conformers (NACs) required for the S(N)2 displacement reaction are members of the IV (CH(3)COO(-)...CH(2)(Cl)CH(2)Cl) family and are formed in the sequence II-->III-->IV-->NAC. The NAC subclass is defined by the COO(-)...CCl contact distance of < or = 3.41 A and the COO(-)...CCl angle of 157-180 degrees. The mole percentage of NACs is 0.16%, based on the 1 M standard state. This result may be compared with 13.4 mole percentage of NACs in the Michaelis complex in the enzyme. It follows that NAC formation in the enzyme is favored by 2.6 kcal/mol. Because reaction coordinates from S to TS, both in water and in the enzyme, pass via NAC (i.e., S --> NAC --> TS), the reduction in the S --> NAC barrier by 2.6 kcal/mol accounts for approximately 25% of the reduction of total barrier in the S --> TS (10.7 kcal/mol). The remaining 75% of the advantage of the enzymatic reaction revolves around the efficiency of NAC --> TS step. This process, based on previous studies, is discussed briefly.