The difference in activity could not be explained by the number and strength of H-bonds between the receptor and the phenolic ligands, as demonstrated by a series of analogs in which the pKa of the phenols was systematically varied. First-principles calculation of the binding energy also failed to explain the greater activity of the para-phenol (1). However, MD simulations of the ligand-receptor complex indicated that the para-phenol (1) produced a more stable ensemble of conformations. Our results support a hypothesis that the ligand binding site of ERa did not evolve to simply a maximize the H-bond interactions with its phenolic hormone.