Computational insights into the aggregation mechanism of human calcitonin.

Human calcitonin (hCT) is a peptide hormone that regulates calcium homeostasis, but its abnormal aggregation can disrupt physiological functions and increase the risk of medullary thyroid carcinoma. To elucidate the mechanisms underlying hCT aggregation, we investigated the self-assembly dynamics of hCT segments (hCT, hCT, and hCT) and the folding and dimerization of full-length hCT through microsecond atomistic discrete molecular dynamics (DMD) simulations. Our results revealed that hCT and hCT predominantly existed as isolated monomers with transient small-sized oligomers, indicating weak aggregation tendencies. In contrast, hCT exhibited robust aggregation capability, forming stable β-sheet aggregates independently. Full-length hCT monomers displayed dynamic helical structures, with dimerization decreasing helix content and enhancing β-sheet formation. The transition to β-sheets in full-length hCT correlated with the loss of helical structure in the hCT region. Conformations with high helical content in hCT corresponded to significantly reduced β-sheet structures across the peptide, underscoring the importance of helical stability in preventing β-sheet conversion. Thus, the development of amyloid-resistant hCT analogues should focus on enhancing helical stability in this crucial region. Overall, our study not only elucidates the aggregation mechanism of hCT but also identifies a critical target for designing drug inhibitors to prevent hCT aggregation.