We describe the application of the molecular dynamics (MD) and molecular mechanics–generalized Born/surface area (MM-GB/SA) approaches to the simulation of the different biological activity of diethylstilbestrol (DES) on two highly homologous nuclear receptors—estrogen receptor (ER-) and estrogen-related receptor (ERR-). DES exerts an agonistic effect against ER-and an antagonistic effect against ERR-. Using the x-ray crystal structures of ER-in the canonical agonist bound form (PDB code: 3ERD) and antagonist bound form (PDB code: 3ERT), ERR-homology models have been constructed for the receptor in two different conformations. MM-GB/SA binding free energy calculations of DES in the ER-and ERR-structures suggest that DES exhibits a greater free energy of binding in the agonist bound conformation of ER-, while the antagonist bound conformation is preferred for ERR-. Further dissection of the free energy contributions coupled with calculation of the ligand binding pocket volume suggests that the van der Waals interactions for DES within the smaller binding pocket volume of ERR-are less favorable and this is the main factor for DES antagonism in ERR-. This approach has potential general applicability to the prediction of the biological activity of nuclear receptor ligands.© 2002 Wiley