MECHANISMS OF INTRAFIBRILLAR CALCIUM PHOSPHATE CLUSTER NUCLEATION IN BONE BIOMINERALIZATION

Medical Mineralogy involves the study of the interaction mechanisms of cells or biomolecules with minerals and aqueous solutions in processes relevant to human health. Mineralogists can uniquely contribute to this field by emphasizing the critical role of the structural, physical and chemical properties of crystals or amorphous solid phases in the thermodynamics or kinetics of the relevant reactions. In our research group, we have been examining the mechanisms of bone biomineralization using state-of-the-art molecular dynamics simulations.

Bone is a hierarchical, composite material of the protein, collagen, and calcium phosphate mineral idealized as hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂). Collagen molecules and higher order structures called collagen fibrils are arranged in strict spatial registry with plate-shaped nanocrystals of hydroxyapatite. Significantly, the calcium phosphate solid phase initially nucleates primarily within specific regions called “hole zones” between collagen molecules within the fibrils. The mechano-biochemical functions of bone depend critically on this architecture. Incredibly, despite six decades of research, the molecular-level mechanisms of calcium phosphate nucleation and crystal growth in bone biomineralization are only poorly understood. We used Molecular Dynamics (MD) to develop the first high-resolution three-dimensional collagen fibril structure from the Å to the 100s of nm length-scale in the presence of hydrating water molecules and Na⁺ and Cl^- ions. Charged amino acid side chains of the collagen molecules were found to be oriented towards the hole zones. Furthermore, state-of-the-art Hamiltonian Replica Exchange MD results showed that Ca²⁺ and phosphate ions were attracted toward the hole zones of the collagen fibrils, because of the specific orientation of the charged amino acid side chains, thus nucleating calcium phosphate clusters in the holes. Structural analysis of the clusters shows that they are amorphous and about 1 nm in size.