Metadynamics Simulations of the pH-Dependent Adsorption of Phosphoserine and Citrate on Disordered Apatite Surfaces: What Interactions Govern the Molecular Binding?

Abstract

Both citrate ions and proteins with phosphorylated side chains are believed to play central roles in bone mineralization. Using metadynamics simulations, we elucidated the pH-dependent surface binding of citrate and O-phospho-l-serine (Pser) at structurally disordered (100) and (001) surfaces of Ca hydroxyapatite (HA), the mother structure of bone mineral. The binding strength of Pser at the (100) surface increased concurrently with the pH value from 4.5 to 14.0 and remained consistently stronger than that at the (001) surface. In contrast, citrate revealed very similar adsorption affinities at both (100) and (001) surfaces throughout 7.4 ≤ pH ≤ 12.3, whereas adsorption at the (100) surface was favored at the lowest (4.5) and highest (14.0) pH values. The two most stable/probable binding modes of citrate involved either a simultaneous anchoring of all three COO– groups such that the molecule caps the HA surface or a “tilted” configuration stemming from the dual binding of the central and one terminal COO– moiety. The surface adsorption of Pser is dominated by its phosphate group, which participates in all significant binding modes, with the two most prominent ones featuring either a co-binding of the PO4 and COO– sites or a linear alignment of the molecule with the surface by the simultaneous anchoring of all three phosphate, carboxy, and amino groups. The latter constitutes the most stable binding mode at the (100) surface for pH = 7.4. We also introduced a straightforward analysis protocol based on Debye–Hückel energies, enabling the quantification of the relative contributions of each functional group of an adsorbed molecule, as well as its underlying interaction energies with the surface. Both the Pser and citrate adsorption occurred predominantly through electrostatic Ca2+–COO–/PO4 2– interactions, along with overall minor H-bond contributions, except for the Pser binding at the PO4-richer (001) HA surface for pH values between 7.4 and 12.3. We highlight the importance of excluding OH groups in the HA surface model to better mimic real nanocrystalline apatite particles and improve the accuracy of the adsorption modeling.

Refined Structures of O-Phospho-l-serine and Its Calcium Salt by New Multinuclear Solid-State NMR Crystallography Methods

“…One example is the complexes between amorphous calcium phosphate (ACP) , and casein in milk. − Strong affinities for binding at CaP surfaces are also manifested by small and negatively charged biomolecules, such as amino acids and the ester of l -serine and phosphoric acid, O -phospho- l -serine (Pser); see Figure a. This feature is confirmed from experimental adsorption studies at (nano)­crystalline HA particles − along with computational modeling, − encompassing very recent findings on the association of Pser molecules and ACP present in Pser-bearing CaP cements (CPCs), which is believed to underpin their bone-adhesive properties. , …”

A facile aqueous production of bisphosphonated-polyelectrolyte functionalized magnetite nanoparticles for pH-specific targeting of acidic-bone cells

“…HAp has the chemical formula of 3Ca 3 (PO 4 ) 2 ·Ca(OH) 2 , and its surface composes of Ca 2+ , OH − , and PO 4 3− ions with the protonated phosphate ions depending on pH and coexisting ions. 61 HAp and Fe 3 O 4 -NCCS-FITC-AL were incubated at 37 °C in saline and the dispersion pH was adjusted to acidic (5.0) and physiological (7.4) conditions. The adhesion ability of the Fe 3 O 4 -NCCS-FITC-AL nanoparticles to HAp surface was studied by SEM and EDX analyses ( Fig.…”

“…These interactions of phosphonates with HAp were reported in previous NMR spectroscopic ( 31 P, 15 N, 13 C, 2 H, and 1 H) and chromatographic studies. 61,63,66,67 This nding revealed that the designed nanosystem has adequate potentials for selective targeting of acidic bone sites.…”

“…In addition, adhered particles were not found in the SEM image groups, in which the P]O remains facing-up and Ca 2+ ions are unveiled by the dissolution of anions. [60][61][62] The Ca 2+ ions on the HAp surface electrostatically attract the carboxylate and bisphosphonate moieties of the Fe 3 O 4 -NCCS-FITC-AL nanocomposite particles. Similar electrostatic interactions were also observed in the previously reported materials bearing bisphosphonate moieties.…”

“…Similar electrostatic interactions were also observed in the previously reported materials bearing bisphosphonate moieties. 61,[63][64][65] In addition, the ammonium and P-OH groups present on the surface of the charge-inverted Fe 3 O 4 -NCCS-FITC-AL nanocomposite particles also contributed to the attraction by the electrostatic and hydrogen-bonding interactions with the surface groups like H 2 PO 4 À , PO 4 3À and P]O moieties of HAp. 3,15 This stronger adherence under the acidic conditions, approximately 140% higher affinity than that under the physiological conditions (Fig.…”