Essence of Small Molecule-Mediated Control of Hydroxyapatite Growth: Free Energy Calculations of Amino Acid Side Chain Analogues

Much effort has been exerted to unravel the bone biomineralization mechanism by which the growth of plate-shaped crystals of hydroxyapatite (HAP) is regulated within a fibrillar collagen matrix. Acidic noncollagenous acidic proteins (NCPs) bearing a large number of carboxylate and phosphorylate amino acid residues are effective regulators of HAP crystal morphology. To reveal the energetic and structural essence of the growth-regulation mechanism, we performed here advanced molecular dynamics simulations to obtain adsorption free energies of side chain analogues (SCAs) of acidic and uncharged polar amino acids as well as the corresponding zwitterionic backbone (BB) fragment and compared the results to those for the entire amino acid molecule. We observed that negatively charged SCAs (phosphoserine in two protonation states, aspartate and glutamate) and the zwitterionic BB preferentially bind to the HAP (100) surface compared to the (001) face, consistent with [100] being the preferred growth direction for ...