title: Non-enzymatic and enzymatic hydrolysis of alkyl halides: a haloalkane dehalogenation enzyme evolved to stabilize the gas-phase transition state of an SN2 displacement reaction.
abstract: The semiempirical PM3 method, calibrated against ab initio HF/6-31+G(d) theory, has been used to elucidate the reaction of 1, 2-dichloroethane (DCE) with the carboxylate of Asp-124 at the active site of haloalkane dehalogenase of Xanthobacter autothropicus. Asp-124 and 13 other amino acid side chains that make up the active site cavity (Glu-56, Trp-125, Phe-128, Phe-172, Trp-175, Leu-179, Val-219, Phe-222, Pro-223, Val-226, Leu-262, Leu-263, and His-289) were included in the calculations. The three most significant observations of the present study are that: (i) the DCE substrate and Asp-124 carboxylate, in the reactive ES complex, are present as an ion-molecule complex with a structure similar to that seen in the gas-phase reaction of AcO- with DCE; (ii) the structures of the transition states in the gas-phase and enzymatic reaction are much the same where the structure formed at the active site is somewhat exploded; and (iii) the enthalpies in going from ground states to transition states in the enzymatic and gas-phase reactions differ by only a couple kcal/mol. The dehalogenase derives its catalytic power from: (i) bringing the electrophile and nucleophile together in a low-dielectric environment in an orientation that allows the reaction to occur without much structural reorganization; (ii) desolvation; and (iii) stabilizing the leaving chloride anion by Trp-125 and Trp-175 through hydrogen bonding.
authors.affiliation: Department of Chemistry, University of California, Santa Barbara, CA 93106, USA.
authors.forename: F C
authors.initials: FC
authors.lastname: Lightstone
authors.forename: Y J
authors.initials: YJ
authors.lastname: Zheng
authors.forename: A H
authors.initials: AH
authors.lastname: Maulitz
authors.forename: T C
authors.initials: TC
authors.lastname: Bruice
mesh_terms: D001218:Aspartame / Q000737:chemistry; D018360:Crystallography, X-Ray; D004795:Enzyme Stability; D005025:Ethylene Dichlorides / Q000737:chemistry*; D006088:Gram-Negative Aerobic Bacteria / Q000737:chemistry / Q000201:enzymology*; D006867:Hydrolases / Q000737:chemistry*; D011487:Protein Conformation
chemical_list: D005025:Ethylene Dichlorides; C024565:ethylene dichloride; D006867:Hydrolases; C046137:haloalkane dehalogenase; D001218:Aspartame