Comparison of Reaction Energetics and Leaving Group Interactions during the Enzyme-Catalyzed and Uncatalyzed Displacement of Chloride from Haloalkanes

Abstract

The S N 2 displacement of chloride from haloalkanes methyl chloride and 1,2-dichloroethane by a series of carboxylate nucleophiles is characterized using ab initio calculations. Comparison of reactivities of methyl chloride and 1,2-dichloroethane in the gas phase and aqueous solution reveals that relative reactivities of these two haloalkanes depend on the reaction environment. 1,2-Dichloroethane is more reactive in the gas phase than methyl chloride, but the order of reactivities is reversed in water. The origin of this effect is analyzed. The activation free energy barrier for the reaction between acetate and 1,2-dichloroethane is 25 kcal/mol (104.6 kJ/mol) in the aqueous environment. A similar reaction is catalyzed by the enzyme haloalkane dehalogenase with activation barrier of 15.3 kcal/mol (64.0 kJ/mol). The origin of this 10 kcal/mol (41.8 kJ/mol) catalytic effect is investigated by calculating how activation free energies depend on the dielectric constant of medium. Comparison of results obtained for the water environment and for the model of the active site environment indicates that a large percentage of this rate acceleration can be explained by the general hydrophobic nature of the active site. The enzyme also uses specific interactions with the chloride atom to facilitate the departure of this leaving group. We find that a single active site tryptophan residue interacts significantly more strongly with the leaving group in the transition state than in the ground state.

The Catalytic Mechanism of Fluoroacetate Dehalogenase: A Computational Exploration of Biological Dehalogenation

“…[23][24][25][26] The activation barrier for the reaction between acetate and DCE was calculated to be about 23 kcal mol À1 in the gas phase. Solvent effects have a pronounced influence on the barrier for the reaction.…”

“…A higher activation energy of about 16 kcal mol À1 is required for the S N 2 displacement of chloride from DCE mediated by haloalkane dehalogenase, in which only two amino acid resides are hydrogen-bonded to the leaving chloride atom. [23][24][25][26][27][28][29][30][31][32] The hydrogen-bonding interactions would be the most important factor that reduces the activation barrier for the cleavage of the strong C À F bond. At low pH, the side chain of Asp104 is hydrogen-bonded to the e-nitrogen of the protonated His271 residue in the transition state.…”

Perspective on Diabatic Models of Chemical Reactivity as Illustrated by the Gas-Phase SN2 Reaction of Acetate Ion with 1,2-Dichloroethane

“…The factors that affect the catalytic efficiency of the enzyme have been the focus of many theoretical studies 12–32. The reactions of several nucleophiles (hydroxide, formate, and acetate) with substrates such as methyl chloride, chloroethane, and DCE have been used to mimic the attack of the Asp124 residue of haloalkane dehalogenase on a haloalkane 13,14,20,22,23. Many theoretical studies of S N 2 reactions in the gas phase and in solution, including those just cited, have made use of ab initio or semiempirical molecular orbital or post-Hartree–Fock electronic structure calculations 33–49.…”

The identification of catalytic pentad in the haloalkane dehalogenase DhmA from Mycobacterium avium N85: Reaction mechanism and molecular evolution

“…Details of the reaction mechanism have been investigated by protein crystallography (Verschueren et al, 1993a;Verschueren et al, 1993b;Verschueren et al, 1993c;Newman et al, 1999;Ridder et al, 1999;Marek et al, 2000;Oakley et al, 2002;Streltsov et al, 2003;Oakley et al, 2004), sitedirected mutagenesis (Pries et al, 1995a;Pries et al, 1995b;Krooshof et al, 1997;Schanstra et al, 1997;Hynkova et al, 1999;Schindler et al, 1999;Bohac et al, 2002), transient kinetics (Schanstra and Janssen, 1996a;Schanstra et al, 1996b;Schanstra et al, 1996c;Bosma et al, 2003;Prokop et al, 2003) and molecular modeling (Damborsky et al, 1997a;Damborsky et al, 1997;Maulitz et al, 1997;Damborsky et al, 1998;Lightstone et al, 1998;Lau et al, 2000;Kmunicek et al, 2001;Bohac et al, 2002;Otyepka and Damborsky, 2002;Shurki et al, 2002;Damborsky et al, 2003;Devi-Kesavan and Gao, 2003;Hur et al, 2003;Kahn and Bruice, 2003;Kmunicek et al, 2003;Silberstein et al, 2003;Soriano et al, 2003;…”