Molecular docking and dynamics simulations in the ligand binding domain of steroid hormone receptors

Abstract

This chapter discusses the experimental study to evaluate the performance of molecular dynamics (MD) simulations when applied to the ligand binding domain of steroid hormone receptors and compare the results with those obtained from flexible ligand docking methods that make use of a single rigid crystal structure. For the MD simulations, only the ligand and the residues that have at least one atom within 8 Å of the ligand were allowed to move (that is, ∼800 out of ∼4000 atoms). From a 100 ps run at 400 K (after a heating phase of 10 ps) coordinate sets were saved every picosecond. After the MD simulation, these coordinate sets were energy minimized (still taking into account the constraints) and the average interaction energy from these 100 frames was calculated. Docking calculations were performed with DOCK 4.0. For validation purposes, MD simulation in the ligand-binding domains of steroid hormone receptors with their co-crystallized ligands were performed—namely, ERα_lere with estradiol, ERa_3erd with diethylstilbestrol (DES), ERβ with genistein, and the progesterone receptor (PR) with progesterone. To assess to which extent the use of a single rigid crystal structure affects the results of a docking calculation, the structures of ERα cocrystallized with estradiol and DES were used in a virtual screening exercise.