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 biomineralization that results in many pathological conditions. Recently, it has been shown in vitro that the growth of hydroxyapatite crystals can be efficiently controlled using phosphocitrate, a naturally occurring compound. Phosphocitrate has been shown also to prevent sticking of cells to hydroxyapatite crystals. However, the molecular mechanism of phosphocitrate interactions with hydroxyapatite crystals was almost entirely unknown due to difficulties in analyzing the X-ray geometry of the unit cell of hydroxyapatite, which exhibits disorder in the hydroxyl ion positions. This study presents the first, to our knowledge, molecular modeling investigations of inhibition of hydroxyapatite crystals. We have used the Generalized Gradient Approximation of Density Functional Theory with the implementation of full periodic boundary conditions to optimize the positions of hydroxyl ions in the unit cell of hydroxyapatite crystal. We have applied molecular modeling to show that phosphocitrate binds to (100) crystal faces of hydroxyapatite, and we have analyzed the nature of stereospecificity of recognition and binding to these planes. We propose that the binding of phosphocitrate to the (100) face of hydroxyapatite induces morphological changes that may lead to diminished crystal growth or to its total cessation, and may also prevent cell sticking to hydroxyapatite. (C) 2000 Elsevier Science B.V. All rights reserved.