Calcium Ions Enable Noncovalent Dimers of Phosphopeptides to Form Self-Oriented Filaments

21 March 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Biomimetic bone regeneration remains a major challenge because of limited understanding of protein-controlled biomineralization to form oriented architecture at molecular level. We unexpectedly found that calcium ions transform dimers of phosphoheptapeptides from nanoparticles to self-oriented filaments via hierarchical self-assembly. This result coincides with the initial stage of biomineralization that calcium ions enable protein dimers to form oriented filaments. To understand the roles of the structures of phosphopeptides for forming the filaments, we synthesized the phosphopeptide analogs with controlled phosphorylation site, hydrophobic interactions, sequences, chirality, and mode of dimerization to evaluate the structural contribution of the phosphopeptides for forming the oriented filaments. Our results confirm that calcium ions interact with noncovalent dimers of the phosphopeptides to form fibrils and enhance interfibrillar interactions to form sheets of parallel fibrils, which further assemble to form oriented filaments. The structures of the analogs indicate that noncovalent dimerization, phosphoserine, and a proline residue prior to phosphoserine in the peptides are critical for the formation of the oriented filaments. High-resolution transmission electron microscopy confirms the interaction between strontium and phosphate ions in the filaments. The work illustrates phosphopeptides as a useful type of molecular building blocks for understanding and mimicking the initiation of phosphoprotein-controlled biomineralization.


calcium ions.

Supplementary materials

Supporting Information for Calcium Ions Enable Noncovalent Dimers of Phosphopeptides to Form Self-Oriented Filaments
Synthetic route, supplementary figures


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