Conformational dynamics of the estrogen receptor alpha: molecular dynamics simulations of the influence of binding site structure on protein dynamics.

We present 158 ns of unrestrained all-atom molecular dynamics (MD) simulations of the human estrogen receptor alpha ligand binding domain (ERalpha LBD) sampling the conformational changes upon binding of estradiol. The pivotal role of His524 in maintaining the protein structure in the biologically active agonist conformation is elucidated. With His524 modeled as the epsilon-tautomer, a conserved hydrogen bond to the ligand is found in the active complex. Helices 3 and 11 are held together by a hydrogen-bonding network from His524 to Glu339 via Glu419 and Lys531, arresting the ligand in the binding pocket and creating the "mouse trap" binding site for helix 12 (H12). The simulations reveal how His524 serves as a communication point between the two. When estradiol is bound, His524 is positioned correctly for the hydrogen bond network to be established. H12 is then positioned for interaction with the co-activator protein, leading to the biologically active complex. The conformational dynamics of ERalpha LBD is further investigated from simulations of antagonist and apo conformations of the protein. These simulations suggest a likely sequence of events for the transition from the inactive apo structure to the transcriptionally active conformation of ERalpha LBD. Stable conformations are identified where H12 is placed neither in the "mouse trap" nor in the co-activator binding groove, as is the case for antagonist structures of ERalpha LBD. Finally, the influence of such conformations on the biological function of ERalpha is discussed in relationship to the interaction with selective estrogen receptor modulators and endocrine-disrupting compounds.