  The estrogen receptor is a nuclear hormone receptor activated by the natural
steroid hormone 17$\beta$-estradiol (E2). Fragment molecular orbital (FMO)
calculations were performed which allowed us to obtain the interaction energy
($E_{int}$) between E2, 17$\alpha$-estradiol (17$\alpha$-E2) and the human
estrogen receptor $\alpha$ ligand-binding domain. In aqueous media the
MP2/6-31G(d) $E_{int}$ was of -85.69 kcal/mol for E2 and -78.11 kcal/mol for
17$\alpha$-E2. Attractive dispersion interactions were observed between ligands
and all surrounding hydrophobic residues. Water molecules were found at the
binding site and strong attractive electrostatic interactions were observed
between the ligands and the Glu 353 and His 524 residues. The essential
dynamics revealed that E2 adapts to the binding site and its motion, in a
sense, synchronizes with the whole receptor; while 17$\alpha$-E2, with its
motion of greater amplitude compared to E2, disturbs the binding site. Perhaps
this feature of the normal substrate is a necessary condition for biological
function. Another important requirement relates to the number of water
molecules at the binding site. Therefore, negative values in $E_{int}$ is a
necessary but not sufficient condition since, it is also necessary to consider
the conformers population that fulfill all the requirements that ensure a
biological response.
