Characterization of ligand type of estrogen receptor by MD simulation and mm-PBSA free energy analysis

Estrogen receptor is a transcription regulator and can bind structurally distinct ligands with full agonistic, SERMs, or full antagonistic properties. Crystal structures of the ER ligand binding domain (LBD)-complexed with full agonists or SERMs show that these ligands induce two different orientations of Helix12 in LBD and generate two different conformations, agonist conformation (A conformation) and AF2 antagonist conformation (B conformation). To understand how ER ligands interact with LBD structurally and energetically, we docked 3 full agonists, 9 SERMs and 2 full antagonists in both the A and B conformation of ERα LBD and performed a 4-step molecular dynamics (MD) simulation on all 28 complexes followed by mm-PBSA binding free energy calculation. We found that all full agonists prefer the A conformation while all SERMs prefer the B conformation. Analysis of the mm-PBSA energies revealed that calculated total binding free energies (delta PBTOT) and the difference of VDW between complex and the sum of receptor of ligands and ligand (delta VDW) have the order of full agonists>SERMs>full antagonists. However, the PB surface term has the order of full antagonists>SERMs>full agonists. We also found that the sum of the RMSD of mainchain atoms of Helix12 and all atoms of ligands in the A conformation is significantly lower for full agonists than that of the other ligands. Together, we conclude that the three types of ER ligands interact with the A and B conformations of ERα LBD differently and same type of ligands interact similarly. These findings will be useful in understanding the mechanism of ER antagonism and can be used in ligand type prediction.