Molecular dynamics of the ERRγ ligand-binding domain bound with agonist and inverse agonist

Estrogen-related receptor gamma (ERR gamma), the latest member of the ERR family, does not have any known reported natural ligands. Although the crystal structures of the apo, agonist-bound, and inverse agonist-bound ligand-binding domain (LBD) of ERR gamma have been solved previously, their dynamic behavior has not been studied. Hence, to explore the intrinsic dynamics of the apo and ligand-bound forms of ERR gamma, we applied long-range molecular dynamics (MD) simulations to the crystal structures of the apo and ligand-bound forms of the LBD of ERR gamma. Using the MD trajectories, we performed hydrogen bond and binding free energy analysis, which suggested that the agonist displayed more hydrogen bonds with ERR gamma than the inverse agonist 4-OHT. However, the binding energy of 4-OHT was higher than that of the agonist GSK4716, indicating that hydrophobic interactions are crucial for the binding of the inverse agonist. From principal component analysis, we observed that the AF-2 helix conformation at the C-terminal domain was similar to the initial structures during simulations, indicating that the AF-2 helix conformation is crucial with respect to the agonist or inverse agonist for further functional activity of ERR gamma. In addition, we performed residue network analysis to understand intramolecular signal transduction within the protein. The betweenness centrality suggested that few of the amino acids are important for residue signal transduction in apo and ligand-bound forms. The results from this study may assist in designing better therapeutic compounds against ERR gamma associated diseases.

Automated summary

In this study, long-range molecular dynamics simulations were used to explore the intrinsic dynamics of ERR gamma. The results revealed that the agonist had more hydrogen bonds with ERR gamma, but the inverse agonist 4-OHT had higher binding energy, indicating the importance of hydrophobic interactions. Furthermore, the study uncovered the intramolecular signal transduction mechanism within the ERR gamma protein. These findings have implications for the design of therapeutic compounds against ERR gamma associated diseases.