Small molecule‐mediated control of hydroxyapatite growth: Free energy calculations benchmarked to density functional theory

Abstract

The unique, plate-like morphology of hydroxyapatite (HAP) nanocrystals in bone lends to the hierarchical structure and functions of bone. Proteins enriched in phosphoserine (Ser-OPO3) and glutamic acid (Glu) residues have been proposed to regulate crystal morphology; however, the atomic-level mechanisms remain unclear. Previous molecular dynamics studies addressing biomineralization have used force fields with limited benchmarking, especially at the water/mineral interface, and often limited sampling for the binding free energy profile. Here, we use the umbrella sampling/weighted histogram analysis method to obtain the adsorption free energy of Ser-OPO3 and Glu on HAP (100) and (001) surfaces to understand organic-mediated crystal growth. The calculated organic-water-mineral interfacial energies are carefully benchmarked to density functional theory calculations, with explicit inclusion of solvating water molecules around the adsorbate plus the Poisson-Boltzmann continuum model for long-range solvation effects. Both amino acids adsorb more strongly on the HAP (100) face than the (001) face. Growth rate along the [100] direction should then be slower than in the [001] direction, resulting in plate-like crystal morphology with greater surface area for the (100) than the (001) face, consistent with bone HAP crystal morphology. Thus, even small molecules are capable of regulating bone crystal growth by preferential adsorption in specific directions. Furthermore, Ser-OPO3 is a more effective growth modifier by adsorbing more strongly than Glu on the (100) face, providing one possible explanation for the energetically expensive process of phosphorylation of some proteins involved in bone biomineralization. The current results have broader implications for designing routes for biomimetic crystal synthesis.

The role of confined collagen geometry in decreasing nucleation energy barriers to intrafibrillar mineralization

“…On the other hand, we previously found that plate-like CaP formed in the confined gap region without intermediate spherical ACP 23 . Similar 2D crystallization can occur by the preferential adsorption of small acidic molecules, such as phosphoserine and citrate, on specific faces of apatite nuclei 38 , 39 . To quantitatively evaluate nucleation in the confined gap region (IM), we developed a model of nucleation in which 2D crystals grow only in the lateral directions with a uniform height (Fig.…”

The role of phosphorylation in dentin phosphoprotein peptide absorption to hydroxyapatite surfaces: a molecular dynamics study

“…The precise role of each of the peptide structures remains unclear. However, as MD is sensitive to initial conditions, we will compare these preliminary MD data with experimental in vitro results to refine the initial conditions before applying others sophisticated computational techniques (9). …”

Method Evaluations for Adsorption Free Energy Calculations at the Solid/Water Interface through Metadynamics, Umbrella Sampling, and Jarzynski's Equality

“…A HAP slab with dimensions of 37.7 Å×34.4 Å×32.3 Å is created as the HAP (100) model surface. The detailed procedure for building the HAP (100) surface can be found elsewhere . Due to the high charge density distribution, the HAP (100) face, as a hydrophilic surface, exhibits strong binding affinity with amino acids and peptides .…”

“…The detailed procedure for building the HAP (100) surface can be found elsewhere . Due to the high charge density distribution, the HAP (100) face, as a hydrophilic surface, exhibits strong binding affinity with amino acids and peptides . For the HAP surface model, we have not considered hydroxylation and protonation of surface ions, which could cause the formation of monohydrogen phosphate/dihydrogen phosphate and removal of a stoichiometric amount of calcium ions.…”

“…Compared with the graphene–water system, the study of the HAP–water interfacial system is more challenging due to strong interactions between the water layer and the Ca 2+ and PO 4 3− ions on the highly charged surface, which impede the exchange of water molecules residing in this adsorption layer with the bulk solution. Our previous studies showed that a small amino acid needs to overcome a free energy barrier of around 26 k B T to penetrate the water layer and bind with the HAP surface. Therefore, the HAP–water system provides a completely distinct interfacial model system from that of the graphene case.…”