Dental enamel remineralization with cementum attachment protein-derived peptides

Remineralization of early dental enamel lesions remains a major challenge due to the difficulty of restoring its highly organized hierarchical architecture. This study investigated the supramolecular behavior of two cementum attachment protein-derived peptides, CAP-p15 and the ultra-short CAP-p5, and their ability to promote enamel remineralization. Peptide self-assembly was analyzed using AlphaFold 3 and molecular dynamics simulations, while their effects on demineralized human enamel were evaluated through complementary structural, chemical, and morphological characterization techniques. The two CAP-derived peptides exhibited distinct self-assembly mechanisms that led to different remineralization pathways. CAP-p15 exhibited cooperative assembly that promoted dense surface mineralization, whereas the ultra-short CAP-p5 maintained a dynamic low-aggregation regime that favored the formation of highly organized nanometric hydroxyapatite crystals. Both peptides restored key chemical signatures of native enamel, as evidenced by the recovery of phosphate and carbonate Raman bands and the restoration of the Ca/P ratio from 1.66 in demineralized enamel to 1.85 and 1.81 after treatment with CAP-p15 and CAP-p5, respectively, closely matching the value measured for sound enamel (1.88). Furthermore, the newly formed mineral layer displayed a hierarchical organization resembling that of natural enamel. These findings highlight the potential of ultra-short cementum-derived peptides as bioinspired agents for enamel remineralization and provide mechanistic insights into peptide-guided formation of hierarchically organized mineral phases.