Molecular dynamics studies of methylmercury interactions with the glucocorticoid receptor protein

Methylmercury (MeHg) is a persistent environmental pollutant whose adverse effects on the human health manifest as impairments to the nervous system. The molecular basis of the damage caused is not yet understood but preliminary experimental data from rat neural stem cells studies suggest that some toxic effects arise through the interference of MeHg with the activity of the ligand-dependent glucocorticoid receptor (GR) protein. Molecular dynamics studies were carried out to investigate MeHg interactions with the GR. A target Cys736 residue was chosen for mercuration based on its proximal location to the ligand-binding site and potential for the interference with the workings of the receptor. The apo and holo systems of two forms, agonistand antagonist-bound structures, were used for the simulation and, additionally, the MeHg-modifed variants. Parameters for MeHg moiety were derived from quantum mechanical calculations at B3LYP and MP2 levels of theory and the simulation conducted in GROMACS. The simulation data suggest that GR can recognise MeHg at Cys736 and respond to it as to a potential ligand, which translates to noticeable changes in the structural conformation and dynamic stability of the protein. The simulation time is insufficient to comment on the nature of that interaction. Currently, the results are inconclusive as to whether MeHg might have agonist or antagonist-like properties, and so are the preliminary experimental data.