Insights into ligand selectivity in estrogen receptor isoforms: Molecular dynamics simulations and binding free energy calculations

Estrogen receptor alpha (ER alpha) and beta (ER beta) are ligand activated transcription factors that have different physiological functions and differential expression in certain tissues. The ligand binding domain of ER beta shares 58% sequence identity with that of ER alpha. However, in the binding pocket there are only two relative residue substitutions. This high similarity at the active site is a great challenge for designing selective estrogen receptor modulators. ER beta is shown to be related to several diseases. To understand the molecular basis of ER beta selectivity, molecular dynamics simulations were carried out for both ER alpha and ER beta complexes. Our simulations revealed the conformational changes at the active site of the ERs and the difference of affinity with ligand. The electrostatic repulsion between the S-delta atom of ER alpha Met421 and the acetonitrile group nitrogen atom of the ligand led to unfavorable binding. The repulsion resulted in the conformational change of the side chain of ER(x Met421, which changed the conformation of both Leu346 and Phe425. These residues changes expanded the volume of binding cavity, which led to unstable binding of the ligand. In addition, ER beta Met336 formed more hydrophobic contacts with the ligand relative to corresponding residue ER alpha Leu384. Furthermore, the binding free energy analysis was shown to be correlated with the previous results determined by experiment. At last, free energy decomposition evidently indicated the contributions of key residues. The present results could help explain the mechanism of ER beta selectivity and may be considered in the design of subtype-selective ligands.