Computational Modeling of a Binding Conformation of the Intermediate l-Histidinal to Histidinol Dehydrogenase

Histidinol dehydrogenase (HDH) is one of the enzymes involved in the l-histidine biosynthesis pathway. HDH is a dimer that contains one Zn²⁺ ion in each identical subunit. In this study, we predicted a possible binding conformation of the intermediate l-histidinal, which is experimentally not known, using a computational modeling method and three potent HDH inhibitors whose structures are similar to that of l-histidinal. At first, a set of the most probable active conformations of the potent inhibitors was determined using two different pharmacophore mapping techniques, the active analogue approach and the distance comparison method. From the most probable active conformations of the three potent inhibitors, the common parts of the l-histidinal structure were extracted and refined by energy minimization to obtain the binding conformation of l-histidinal. This predicted conformation of l-histidinal agrees with an experimentally determined conformation of l-histidine in a single crystal, suggesting that it is an experimentally acceptable conformation. The capability in this conformation to coordinate a Zn²⁺ ion was examined by comparing the spatial relative geometry of its functional groups with those of ligands that coordinate with a Zn²⁺ ion in Zn proteins of the Protein Data Bank. This comparison supported our predicted conformation.