Molecular Dynamics Simulation Studies on the Modulation of Vitamin D Receptor Activity by Agonists and Antagonists

Abstract

Molecular dynamics (MD) simulations of vitamin D receptor (VDR) ligand complexes have been carried out to explain and predict ligands' functional behavior. Elevated simulation temperature, simulated annealing, locally enhanced sampling method, and targeted dynamics were used to speed up the sampling of the conformational space in MD simulations. In addition, self-organizing map and Sammon's mapping algorithm was applied to group and visualize receptor movement upon ligand binding. It was shown that the degree of structural order in the carboxy-terminal α-helix inversely correlated with the strength of the antagonistic activity of the ligand and that a two-side chain analog of vitamin D functions as a potent agonist to the VDR despite its significantly increased volume. Binding of novel nonsteroidal VDR agonists was also investigated. Simulation results were combined with extensive experimental data. In this work theoretical and experimental studies were fruitfully combined to investigate complex receptor regulation.