[Paper Review] Ab initio Investigation of Adsorption Characteristics of Bisphosphonates on Hydroxyapatite (001) Surface

Mun-Hyok Ri, Yong-Man Jang+2 more|arXiv (Cornell University)|Apr 26, 2016

Bone health and treatments29 references3 citations

TL;DR

This first-principles study investigates the adsorption of seven bisphosphonates (BPs) on hydroxyapatite (001) surfaces using density functional theory. It reveals that pamidronate exhibits the highest adsorption energy (-3.33 eV), followed by alendronate (-3.21 eV), due to strong hydrogen bonding and electron donation from nitrogen and hydroxyl groups, with results aligning with experimental affinity rankings and confirming adsorption energy as the key determinant of BP binding affinity to bone mineral.

ABSTRACT

The structures of some bisphosphonates (clodronate, etidronate, pamidronate, alendronate, risedronate, zoledronate, minodronate) were obtained and analyzed, and their adsorption energies onto hydroxyapatite (001) surface were compared to find out ranking order of binding affinity, which shows that the adsorption energy is the largest for pamidronate, followed by alendronate, zoledronate, clodronate, ibandronate, the lowest for minodronate and etidronate.

Motivation & Objective

• To determine the relative binding affinities of key bisphosphonates (BPs) for hydroxyapatite (HAP), the primary mineral in bone.
• To elucidate the atomic-scale mechanisms governing BP adsorption on HAP(001), including electronic and geometric factors.
• To correlate computed adsorption energies with experimental binding affinity rankings to validate computational predictions.
• To analyze charge transfer and orbital interactions (HOMO-LUMO) that stabilize BP-HAP complexes.

Proposed method

• First-principles density functional theory (DFT) calculations were performed using the generalized gradient approximation (GGA) with the PBE functional.
• Periodic slab models of the HAP(001) surface were constructed, with BPs adsorbed on the calcium-terminated surface.
• Adsorption energies were calculated as E_ads = E_{BP+HAP} - (E_{BP} + E_{HAP}), with energy convergence to 10^{-6} eV.
• Hirshfeld charge analysis was used to examine charge redistribution upon adsorption, assessing electron donation and surface stabilization.
• Molecular orbital analysis (HOMO and LUMO) identified electron donor/acceptor roles of functional groups like -OH and -NH2.
• Adsorption geometries were optimized and analyzed for hydrogen bonding between BP -OH and HAP surface oxygen atoms.

Experimental results

Research questions

• RQ1 What is the relative adsorption energy order of bisphosphonates on the HAP(001) surface, and how does it compare to experimental rankings?
• RQ2 How do functional groups (e.g., -OH, -NH2, heterocyclic nitrogen) influence the electronic and geometric structure of BP-HAP complexes?
• RQ3 What is the role of hydrogen bonding between BP hydroxyl groups and HAP surface oxygen atoms in stabilizing adsorption?
• RQ4 How does charge transfer, as quantified by Hirshfeld analysis, affect the stability of the BP-HAP interface?
• RQ5 To what extent do HOMO-LUMO interactions explain the enhanced binding affinity of nitrogen-containing BPs?

Key findings

• Pamidronate exhibits the highest adsorption energy (-3.33 eV), followed by alendronate (-3.21 eV), zoledronate (-2.92 eV), clodronate (-2.35 eV), ibandronate (-2.31 eV), risedronate (-2.25 eV), minodronate (-2.17 eV), and etidronate (-2.17 eV).
• The computed adsorption energy ranking closely matches experimental affinity orders from NMR, FPLC, and competitive binding assays, validating the computational model.
• Hydrogen bonding between the hydroxyl group of BPs and surface oxygen atoms of HAP is a key stabilizing interaction in the adsorption geometry.
• Hirshfeld charge analysis shows that the adsorption process redistributes charge, stabilizing the HAP surface by shifting its charge distribution toward that of the bulk crystal.
• Nitrogen atoms in nitrogen-containing BPs (e.g., pamidronate, alendronate) act as electron donors during adsorption, as indicated by HOMO-LUMO analysis.
• The P–C–P backbone structure is sensitive to R2 group variations, with nitrogen-containing R2 groups significantly enhancing binding affinity.