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

MD simulations of vitamin D receptor (VDR) complexed with ligands having structurally and functionally varying properties have been carried out to investigate atomic level mechanisms responsible for the ligands’ functional behavior. 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. Simulations showed that the second side chain can choose between two binding positions. Binding of novel nonsteroidal VDR agonists was also investigated. Simulation results were combined with extensive experimental data. This work nicely demonstrates that MD simulations are capable of revealing the subtle differences there exists between VDR activating and deactivating ligands, and how theoretical and experimental work may be fruitfully combined to study complex receptor regulation.