The catalytic formation of leukotriene C₄: a critical step in inflammatory processes

Abstract

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.

The CHARMM–TURBOMOLE interface for efficient and accurate QM/MM molecular dynamics, free energies, and excited state properties

“…As QM calculations are much more computationally demanding than MM calculations, these hybrid models are far more efficient than the equivalent pure QM model. Current QM/MM models typically have QM regions that include 10–100 atoms and MM regions that include hundreds or thousands of atoms …”

Developing adaptive QM/MM computer simulations for electrochemistry

“…In general, such methods use embedding schemes to encapsulate the chemically active site in a small region described by a relatively high level of theory within a bulk environment which is described by a comparatively low level of theory (e.g., classical force fields). These approaches frequently focus on research topics in medicinal chemistry and biochemistry . Other studies focus on solution chemistry problems and materials research, left out the quantifications and—to the best of our knowledge—no study has yet focused on problems in electrochemical energy storage.…”