Fragment molecular orbital-interfragment interaction energy calculations of the vitamin D receptor (VDR)/1 alpha,25-dihydroxyvitamin D-3 complex were utilized to assign functions of key residues of the VDR. Only one residue forms a significant interaction with the corresponding hydroxy group of the ligand, although two residues are located around each hydroxy group. The degradation of binding affinity for derivatives upon removal of a hydroxy group is closely related to the trend in the strength of the hydrogen bonds. Type 11 hereditary rickets due to an Arg274 point mutation is caused by the lack of the strongest hydrogen bond. (c) 2006 Elsevier B.V. All rights reserved.