How Charged Amino Acids Regulate Nucleation of Biomimetic Hydroxyapatite Nanoparticles on the Surface of Collagen Mimetic Peptides: Molecular Dynamics and Free Energy Investigations

Biomineralization is the concept of biologically controlled or induced aggregations of salt ions, which is one of the most widely spread phenomena in nature. The formation of bones is one of the prototypical biomineralization processes which involves the association of calcium and phosphate ions to generate the apatite crystals on collagen fibers. In this work, the nucleation mechanism was investigated from a microscopic point of view using molecular dynamics (MD) and metadynamics simulations. Compared to other charged residues, the arginine residue was confirmed to stay at the dominant position when promoting the nucleation of calcium phosphate clusters. Based on the free energy profiles for the association of ion pairs, we combine thermodynamics and kinetics work together to affect the efficiency of nucleation of calcium phosphate in the aqueous phase. In addition, the unusual like-charge cation pair formed between two adjacent arginines could lead to losing the function of inducing calcium phosphate clusters generated on the collagen protein surface. Our study might provide a way to regulate the growth or nucleation of hydroxyapatite via a protein engineering technique, which is also helpful to further design new biomaterials.