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Human bone sialoprotein (BSP) is an essential component of the extracellular matrix of bone. It is thought to be the primary nucleator of hydroxyapatite crystallization, and is known to bind to hydroxyapatite, collagen, and cells. Mature BSP shows extensive post-translational modifications, including attachment of glycans, sulfation, and phosphorylation, and is highly flexible with no specific 2D or 3D structure in solution or the solid state. These features have severely limited the experimental characterization of the structure of this protein. We have therefore developed a 3D structural model for BSP, based on the available literature data, using molecular modelling techniques. The complete model consists of 301 amino acids, including six phosphorylated serines and two sulfated tyrosines, plus 92 N- and O-linked glycan residues. A notable feature of the model is a large acidic patch that provides a surface for binding Ca2+ ions. Density functional theory quantum calculations with an implicit solvent model indicate that Ca2+ ions are bound most strongly by the phosphorylated serines within BSP, along with reasonably strong binding to Asp and Glu, but weak binding to His and sulfated tyrosine. The process of early hydroxyapatite nucleation has been studied by molecular dynamics on an acidic surface loop of the protein; the results suggest that the cationic nature of the loop promotes nucleation by attracting Ca2+ ions, while its flexibility allows for their rapid self-assembly with PO43− ions, rather than providing a regular template for crystallization. The binding of a hydroxyapatite crystal at the protein's acidic patch has also been modelled. The relationships between hydroxyapatite, collagen and BSP are discussed.