(50d) Using Enhanced Sampling Methods to Study the Behavior of Osteocalcin on Mineral Surfaces

Biomineralization, the natural process by which organisms produce minerals, motivates the design of nature-inspired materials applicable in bone and dental regeneration.¹ Osteocalcin (dhOC), a natural non-collagenous protein abundantly found in bone and dentin, exhibits a high affinity for mineral surfaces such as calcium-phosphate rich hydroxyapatite (HAP) – a naturally occurring form of calcium apatite, and a major component of bone. It is understood the dhOC plays a prominent role in bone mineralization. However, the mechanisms and energetic driving forces that govern these interactions remain difficult to probe with experiments alone. It’s affinity towards mineral surfaces has been prescribed to highly favorable binding between glutamic acid and calcium.¹ The presence of three potassium-dependent post-translational modification of glutamic acid (GLA) residues in the α-1 helix of dhOC are believed to be important for regulating and strengthening binding of dhOC to HAP². Because modified, partially modified, and unmodified variations of dhOC are all naturally occurring, we are motivated to investigate how the structural or thermodynamic properties of dhOC α-1 change as a function of post-translational modifications. Further, the interactions between dhOC and its modifications on common implant materials such as silica (SiO₂) and titania (TiO₂) are much less understood, prompting additional interest in investigating these modifications as a function of surface effects.

This talk will highlight our application of enhanced sampling molecular dynamics methods to evaluate binding free energies and structural information concerning the α-1 helix of dhOC bound to HAP, TiO₂, and SiO₂ in unison with experimental studies. Using this comprehensive protocol, we hope to paint a complete picture of the of this protein’s role in binding to organic materials.

References

1. Palmer, L. C., Newcomb, C. J., Kaltz, S. R., Spoerke, E. D. & Stupp, S. I. Biomimetic Systems for Hydroxyapatite Mineralization Inspired By Bone and Enamel. Chem. Rev. 108, 4754–4783 (2008).
2. Malashkevich, V. N., Almo, S. C. & Dowd, T. L. X-ray Crystal Structure of Bovine 3 Glu-Osteocalcin. Biochemistry 52, 8387–8392 (2013).