Simulations of the Estrogen Receptor Ligand-Binding Domain:  Affinity of Natural Ligands and Xenoestrogens

We have carried out molecular dynamics (MD) simulations and free energy calculations on the α-subtype of the human estrogen receptor ligand-binding domain (ERα LBD) complexed with a number of known agonists and putative xenoestrogens. Our dynamical simulations of ligand−receptor complexes underscore the highly structured nature of the complex and offer some interesting insights into the structure−activity relationship (SAR) for these ligands. With traditional thermodynamic integration (TI) calculations, we calculate relative binding free energies for three known agonists, in good agreement with experimental values. The sheer number of possible xenoestrogenic compounds makes an approach using traditional free energy calculations unfeasible. Instead, we have made use of a single-step perturbation methodology that allows the calculation of relative free energies for a large number of related polyaromatic hydrocarbons (PAHs) from a single simulation. Our results show good (maximum deviation 3.3 kJ mol-1) agreement with experimental data, suggesting the possibility of large-scale xenoestrogen screening in silico to obtain strongly estrogenic compounds for subsequent experimental testing.