Molecular Dynamics and Free Energy Studies on the Drosophila Melanogaster and Leptinotarsa Decemlineata Ecdysone Receptor Complexed with Agonists: Mechanism for Binding and Selectivity.

The ecdysone receptor is a nuclear hormone receptor that plays a pivotal role in insect metamorphosis and development. To address the molecular mechanisms of binding and selectivity, the interactions of two typical agonists Ponasterone A and 20-Hydroxyecdysone with Drosophila melanogaster (DME) and Leptinotarsa decemlineata ecdysone (LDE) receptors were investigated by homology modeling, molecular docking, molecular dynamics simulation and thermodynamic analysis. We discover that: 1) the L5-loop, L11-loop and H12 helix for DME, L7-loop and L11-loop for LDE are more flexible, which affect the global dynamics of the ligand binding pocket, thus facilitating the ligand recognition of ecdysone receptor; 2) several key residues (Thr55/Thr37, Phe109/Phe91, Arg95/Arg77, Arg99/Arg81, Phe108/Leu90 and Ala110/Val92) are responsible for the binding of the proteins; 3) the binding free energy is mainly contributed by the van der Waals forces compared with the electrostatic interactions of ligand and receptor; 4) the computed binding free energy difference between DME-C1 and LDE-C1 is -1.55 kcal/mol, explains that C1 can form many more interactions with the DME; 5) residues Phe108/Leu90 and Ala110/Val92 have relatively position and orientation difference in the two receptors, accounting most likely for the ligand selectivity of ecdysone receptor from different orders of insects. The present study underscores the expectation that different insect pests should be able to discriminate among compounds from different as yet undiscovered compounds, the results firstly show a structural and functional relay between the agonists and receptors (DME and LDE), which can provide an avenue for development of target-specific insecticides.