Paper Citing NAMD - Abstract
MacDonald, Corey A.; Bushnell, Eric A. C.; Gauld, James W.; Boyd, Russell J.
The catalytic formation of leukotriene C-4: a critical step in inflammatory processes
PHYSICAL CHEMISTRY CHEMICAL PHYSICS, 16:16284-16289, 2014
Leukotrienes (LT) are a family of drug-like molecules involved in the pathobiology of bronchial asthma and are responsible for smooth muscle contraction. Leukotriene C-4 synthase (LTC4S) is a nuclear-membrane enzyme responsible for the conjugation of leukotriene A(4) (LTA(4)) to glutathione to form LTC4, a cysteinyl leukotriene. In this study, the mechanism of LTA(4) 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 LTA(4): '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 LTA(4). In particular, the thiolate of glutathione acts as a nucleophile attacking C-6 of LTA(4) forming a S-C-6 bond. Concomitantly, a proton is transferred from the guanidinium of Arg(31) 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.
