Molecular modeling of inhibition of hydroxyapatite by phosphocitrate

Hydroxyapatite is one of the most important minerals in the human body. It constitutes almost the entire mineral phase of bones and tooth enamel. Its ubiquity, however, sometimes may lead to cases of unwanted biomineralizatio n that results in many pathological conditions. Recently, it has been shown in vitro that the growth of hydroxyapatite crystals can be efficiently con trolled using phosphocitrate, a naturally occurring compound. Phosphocitrat e has been shown also to prevent sticking of cells to hydroxyapatite crysta ls. However, the molecular mechanism of phosphocitrate interactions with hy droxyapatite crystals was almost entirely unknown due to difficulties in an alyzing the X-ray geometry of the unit cell of hydroxyapatite, which exhibi ts disorder in the hydroxyl ion positions. This study presents the first, to our knowledge, molecular modeling investi gations of inhibition of hydroxyapatite crystals. We have used the Generali zed Gradient Approximation of Density Functional Theory with the implementa tion of full periodic boundary conditions to optimize the positions of hydr oxyl ions in the unit cell of hydroxyapatite crystal. We have applied molec ular modeling to show that phosphocitrate binds to (100) crystal faces of h ydroxyapatite, and we have analyzed the nature of stereospecificity of reco gnition and binding to these planes. We propose that the binding of phospho citrate to the (100) face of hydroxyapatite induces morphological changes t hat may lead to diminished crystal growth or to its total cessation, and ma y also prevent cell sticking to hydroxyapatite. (C) 2000 Elsevier Science B .V. All rights reserved.