Computational evidence for the degradation mechanism of haloalkane dehalogenase LinB and mutants of Leu248 to 1-chlorobutane

Abstract

The catalytic degradation ability of the haloalkane dehalogenase LinB toward 1-chlorobutane (1-CB) was studied using a combined quantum mechanics/molecular mechanics (QM/MM) approach. Two major processes are involved in the LinB-catalyzed removal of halogens: dechlorination and hydrolyzation. The present study confirmed the experimentally proposed reaction path at the molecular level. Moreover, based on nucleophilic substitution mechanism (SN2 reaction), dechlorination was found to be the rate-determining step of the entire reaction process. In this study, the Boltzmann-weighted average barrier for dechlorination was determined to be 17.0 kcal mol-1, which is fairly close to the experimental value (17.4 kcal mol-1). The state of His107 and the influence of Leu248 on the dechlorination process were also explored. In addition, an intriguing phenomenon was discovered: the potential energy barrier decreased by 7.5 kcal mol-1 when the Leu248 residue was mutated into Phe248. This discovery might be of great help to design new mutant enzymes or novel biocatalysts.

Multiscale QM/MM modelling of catalytic systems with ChemShell

“…[128][129][130] Environmental chemistry is an increasingly prominent topic for QM/MM simulations, which have been used to investigate biodegradation of pesticides, [131][132][133] plastics, 134,135 and other hazardous pollutants. [136][137][138][139][140][141][142] Feng et al used ChemShell to study the degradation of polyethylene terephthalate (PET), 143 comparing the common features of reactions catalysed by the enzymes IsPETase and IsMHETase and analysing the structural characteristics that affect catalytic activity, pointing the way to the design of more efficient enzymes for plastic recycling.…”

Catalytic Mechanism for 2,3-Dihydroxybiphenyl Ring Cleavage by Nonheme Extradiol Dioxygenases BphC: Insights from QM/MM Analysis

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