Calcium Phosphate Prenucleation Complexes in Water by Means of ab Initio Molecular Dynamics Simulations

Giulia Mancardi,Umberto Terranova,Nora H De Leeuw

doi:10.1021/acs.cgd.6b00327

Abstract

The nucleation of calcium phosphates, the main inorganic component of bone and tooth tissues, is thought to proceed by aggregation of prenucleation clusters recently identified as calcium triphosphate complexes. We have performed ab initio molecular dynamics simulations to elucidate their structures and stabilities in aqueous solution. We find the calcium to be seven-coordinated by two water molecules, two bidentate phosphates, and one monodentate phosphate. Free energy results obtained using umbrella sampling simulations show that the complex with a Ca/P ratio of 1:3 is the most energetically favored and more thermodynamically stable than the free ions.

Highlights

Calcium phosphate (CaP) is the major inorganic component of biological hard tissues, where it is mainly present in the form of hydroxyapatite (nominally, Ca10(OH)2(PO4)[6])
XANES and XRD experiments of the early stages of CaP crystallization have suggested that an idealized cluster with the formula Ca9(PO4)6(H2O)[30] may act as the structural unit of amorphous calcium phosphate (ACP),[7] whereas the most abundant clusters detected in solution at the early stage of nucleation have been reported to be of the form Ca(η2−PO43−)2L2 (L = H2O or η1−PO43−, where η1 and η2 stand for monodentate and bidentate binding of the phosphate groups).[8]
During our NVT dynamics starting from the prenucleation complexes (PNCs) depicted in Figure 1(I), two water molecules entered the first coordination sphere and during the simulation never exchanged with other water molecules

Summary

Introduction

Calcium phosphate (CaP) is the major inorganic component of biological hard tissues, (e.g., bone and teeth), where it is mainly present in the form of hydroxyapatite (nominally, Ca10(OH)2(PO4)[6]). CaP is responsible for pathological crystallization, leading to several common diseases including atherosclerosis, dental caries, osteoporosis, and kidney stones.[1] Hydroxyapatite[2] originates from an amorphous calcium phosphate (ACP) precursor in a process of dissolution and reprecipitation.[3] In the 1970s, Posner and Betts proposed that structural units of the form Ca9(PO4)[6] would aggregate randomly, with the intercluster space filled with water, into larger spherical particles of ACP.[4] More recently, a clustergrowth model for the formation of ACP was proposed,[5] and aggregating clusters were found to be present in body fluids even before nucleation.[6] XANES and XRD experiments of the early stages of CaP crystallization have suggested that an idealized cluster with the formula Ca9(PO4)6(H2O)[30] may act as the structural unit of ACP,[7] whereas the most abundant clusters detected in solution at the early stage of nucleation have been reported to be of the form Ca(η2−PO43−)2L2 (L = H2O or η1−PO43−, where η1 and η2 stand for monodentate and bidentate binding of the phosphate groups).[8] Habraken et al.[9] showed that the prenucleation complexes (PNCs), aggregating in solution to form polymeric structures, have the formula [Ca(η2−HPO4)3]4−. A Posner’s cluster can be seen as two deprotonated PNCs in which all negative charges are compensated by complexing calcium ions. To explain the formation of ACP at the supersaturations used in their experiment, the PNCs were proposed to have an excess free energy over that of free ions, which dramatically reduces the nucleation barrier.[10]

Methods

Results

Conclusion