The mechanism to fix helix 12 (H12) in the agonist/antagonist position, which is involved in controlling transcriptional activation, of the human estrogen receptor α ligand binding domain (hERαLBD) is studied by using fragment molecular orbital calculations at the Møller-Plesset second-order perturbation levels to analyze inter-fragment interaction energies (IFIEs), electrostatic potentials (ESPs), and atomic charges. The mutually attractive and complementary relationships between H12 and highly conserved Lys529/Lys362 are shown through the IFIEs and ESPs. The highly conserved Lys529 and Lys362 are found to have strong attractive interactions with the anionic residues of H12 in the agonist and antagonist positions, respectively, thus playing roles of charge clamps to fix H12. Additionally, intramolecular interactions between the neutral residues of H12 including the LXXML motif and the other part of hERα are strengthened by the hydrogen bonds and polarization. It is noted that the highly conserved Asp351 forms a hydrogen bond with Leu540 of H12 in the hERα-agonist complex, while it is also involved in stabilization of ligand binding in the hERα-antagonist complex. The charges of residues at the interface between H12 and the other part of hERα approach approximately neutral upon forming the agonist/antagonist binding conformation so as to relax the electrostatic repulsion caused by the negative charges of H12 and the other part of hERα. Our observations would thus provide useful information to control the H12 position for regulation of transcription in hERα and other nuclear receptors.