Computational Insights into the Mechanism of Ligand Unbinding and Selectivity of Estrogen Receptors

Jie Shen, Weihua Li, Guixia Liu, Yun Tang, and Hualiang Jiang

Abstract

Estrogen receptors (ER) belong to the nuclear receptor superfamily, and two subtypes, ERR and ER, have
been identified to date. The differentiated functions and receptor expressions of ERR and ER made it attracted
to discover subtype-specified ligands with high selectivity. However, these two subtypes are highly homologous
and only two residues differ in the ligand binding pocket. Therefore, the mechanism of ligand selectivity has
become an important issue in searching selective ligands of ER subtypes. In this study, steered molecular
dynamics simulations were carried out to investigate the unbinding pathways of two selective ER ligands
from the binding pocket of both ERR and ER, which demonstrated that the pathway between the H11 helix
and the H7∼H8 loop was the most probable for ligand escaping. Then potentials of mean force for ligands
unbinding along this pathway were calculated in order to gain insights into the molecular basis for energetics
of ligand unbinding and find clues of ligand selectivity. The results indicated that His524/475 in ERR/ER
acted as a “gatekeeper” during the ligand unbinding. Especially, the H7∼H8 loop of ER acted as a polar
“transmitter” that controlled the ligand unbinding from the binding site and contributed to the ligand selectivity.
Finally, the mechanism of ligand selectivity of ER subtypes was discussed from a kinetic perspective and
suggestions for improving the ligand selectivity of ER were also presented. These findings could be helpful
for rational design of highly selective ER ligands.