A computational study of the dechlorination of β-hexachlorocyclohexane (β-HCH) catalyzed by the haloalkane dehalogenase LinB

•β-Hexachlorocyclohexane binds effectively to the active site of LinB.•Asn38 and Trp109 interact with the departing chloride ion.•Dechlorination of β-HCH by LinB occurs via concerted mechanism.•DFT:CHARGE/MM method provides activation barriers that agrees with the experiment.•1-Chlorobutane can change its binding orientation from productive to non-productive.

LinB, a haloalkane dehalogenase from Sphingomonas paucimobilis UT26, is known to metabolize halohydrocarbons to halide ions and the respective alcohols. Its broad substrate specificity allowed its consideration for bioremediation. Herein, we have shown its catalytic action toward β-hexachlorocyclohexane (β-HCH) – an example of large-size substrates that can be accommodated in its active site. We have analyzed the capability of combined QM/MM schemes to describe in detail the SN2 dechlorination reaction between β-HCH and Asp108 in the active site of LinB. Free energy surfaces have been calculated using one and two dimensional potentials of mean force (PMF) obtained at the PM3/MM (MM = amberff99SB, TIP3P) level of theory. The overestimated energetic barriers by the PM3 Hamiltonian were corrected using a DFT functional (M06-2X). The resulted activation energies (16 and 19 kcal mol−1 from 1D and 2D-PMF profiles, respectively) for the dechlorination reaction of β-HCH in the active site of LinB enzyme are in qualitative agreement with the experimentally determined value of 17 kcal mol−1. The binding of β-HCH to the active site of LinB has been compared to the binding of smaller 1-chlorobutane (1-CB) and larger δ-hexabromocyclododecane (δ-HBCD).

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