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Leukotrienes (LT) are a family of drug-like molecules involved in the pathobiology of bronchial asthma and are responsible for smooth muscle contraction. Leukotriene C4 synthase (LTC4S) is a nuclear-membrane enzyme responsible for the conjugation of leukotriene A4 (LTA4) to glutathione to form LTC4, a cysteinyl leukotriene. In this study, the mechanism of LTA4 binding by LTC4S has been computationally examined. More specifically, docking and molecular dynamics simulations were used to gain insight into the substrate-bound active site. These studies identified two possible orientations for bound LTA4: 'tail-to-head' and 'head-to-tail'. An ONIOM(QM/MM) approach was then used to elucidate the mechanism by which glutathione may add to LTA4. In particular, the thiolate of glutathione acts as a nucleophile attacking C6 of LTA4 forming a S-C6 bond. Concomitantly, a proton is transferred from the guanidinium of Arg31 to the epoxide ring oxygen. This results in opening of the epoxide ring and stabilization of the LTC4 product complex. Within the present computational methodology the 'tail-to-head' orientation appears to be the most likely substrate orientation.