Molecular mechanisms for intrafibrillar collagen mineralization in skeletal tissues

The critical role of the self-assembled structure of collagen in skeletal mineralization is long recognized, yet the angstrom to tens of nanometers length-scale nucleation mechanism of calcium phosphate mineral (Ca-P-i) remains unclear. Here, by constructing three-dimensional structure of collagen fibril, we report direct computational evidence of intrafibrillar Ca-P-i nucleation in the collagen matrix and illustrate the crucial role of charged amino acid sidechains of collagen molecules in nucleation. The all-atom Hamiltonian replica exchange molecular dynamics simulation shows that these charged sidechains are oriented toward the fibril hole zones and significantly template nucleation with amorphous Ca-P-i phase, similar to 1.3-1.6 nm in size, thus explaining the empirical observations that Ca-P-i nucleates principally in these regions. We also show that the low water density of about 0.70 g cm(-3) in these zones may further benefit nucleation by lowering the enthalpic penalty for ion desolvation. This work provides insight, at the atomistic level, into the nucleation mechanism of bone crystals within a collagen matrix for understanding mineral deposition, interpreting mineralization experiments and guiding the design of new implantable materials. (C) 2014 Elsevier Ltd. All rights reserved.