Theoretical studies on the structural rearrangement of ligand binding pocket in human vitamin D receptor

The structural rearrangement of the ligand binding domain (LBD) of human Vitamin D receptor (hVDR) complexed with 1α, 25‐dihydroxyvitamin D₃ (natural ligand) and its analogues (denoted as b and c ) was studied by molecular dynamics (MD) simulations. MD simulations revealed that these ligands could induce different structural changes of LBD, in which 1α, 25‐dihydroxyvitamin D₃ only led to a minute change, suggesting that LBD adopted its canonical active conformation upon binding the natural ligand, while b and c could provoke a clear structural rearrangement of the LBD. In complex of hVDR‐LBD/ b , it is found that helix 6 (H6) and subsequent loop 6‐7 shift outward and the last turn of H11 shifts away from H12, which generate a new cavity at the bottom of binding pocket to accommodate the extra butyl group on the side chain of ligand b . As for hVDR‐LBD/ c , the steric exclusion of the second side chain of ligand c makes the N‐terminal of H7 move outsides and C‐terminal of H11 close to H12, expanding the bottom of the pocket. These calculation results agree well the experimental observations. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011