Ligand chirality can affect histidine protonation of vitamin-D receptor: ab initio molecular orbital calculations in water

Interacting structures between hVDR residues and ligand 2 depending on the protonation states of His305 and His397 [Display omitted] •We investigated specific interactions between vitamin D receptor (VDR) and its ligand.•Ab initio fragment molecular orbital (FMO) method was used for calculations.•Stable protonation states of His residues in VDR were precisely determined by FMO.•The difference in chirality of ligands causes the difference in His protonations. Vitamin D is recognized to play important roles in the onset of immunological diseases as well as the regulation of the amount of Ca in the blood. Since these physiological actions caused by active vitamin D are triggered by the specific interaction between the vitamin D receptor (VDR) and active vitamin D, many types of compounds have been developed as potent ligands against VDR. It was found that the binding affinity between VDR and its ligand depends significantly on the chirality of the ligand. However, the reason for the dependence has, thus far, not been elucidated. In the present study, we investigated the specific interactions between VDR and some ligands with different chirality, using ab initio fragment molecular orbital (FMO) calculations. The FMO results reveal that two histidine residues of VDR contribute significantly to the binding between VDR and ligand and that their protonation states can affect the specific interactions between VDR and ligand. We therefore considered other possible protonation states of these histidine residues and determined their most stable states, using the ab initio FMO calculations. The results illustrate the possibility that the difference in the chirality of a ligand can induce the change in protonation states of the histidine residues of VDR existing near the ligand. This finding provides an important warning that the protonation states of histidine residues existing near the ligand should be considered more precisely in the molecular simulations for investigating the specific interactions between protein and ligand.