Computational insights into the aggregation mechanism of human calcitonin

Fengjuan Huang; Xinjie Fan; Huan Xu; Zhongyue Lv; Yu Zou; Jiangfang Lian; Feng Ding; Yunxiang Sun

doi:10.1016/j.ijbiomac.2025.139520

Computational insights into the aggregation mechanism of human calcitonin

Int J Biol Macromol. 2025 Jan 4:139520. doi: 10.1016/j.ijbiomac.2025.139520. Online ahead of print.

Authors

Fengjuan Huang¹, Xinjie Fan², Huan Xu², Zhongyue Lv³, Yu Zou⁴, Jiangfang Lian⁵, Feng Ding⁶, Yunxiang Sun⁷

Affiliations

¹ Ningbo Institute of Innovation for Combined Medicine and Engineering (NIIME), The Affiliated LiHuiLi Hospital of Ningbo University, Ningbo 315211, China.
² School of Physical Science and Technology, Ningbo University, Ningbo 315211, China.
³ Department of Neurology, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang 315040, China.
⁴ Department of Sport and Exercise Science, Zhejiang University, Hangzhou 310058, China.
⁵ Ningbo Institute of Innovation for Combined Medicine and Engineering (NIIME), The Affiliated LiHuiLi Hospital of Ningbo University, Ningbo 315211, China. Electronic address: hjmpin@163.com.
⁶ Department of Physics and Astronomy, Clemson University, Clemson, SC 29634, United States. Electronic address: fding@clemson.edu.
⁷ School of Physical Science and Technology, Ningbo University, Ningbo 315211, China; Department of Physics and Astronomy, Clemson University, Clemson, SC 29634, United States. Electronic address: sunyunxiang@nbu.edu.cn.

PMID: 39761900
DOI: 10.1016/j.ijbiomac.2025.139520

Abstract

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_1-14, hCT_15-25, and hCT_26-32) and the folding and dimerization of full-length hCT_1-32 through microsecond atomistic discrete molecular dynamics (DMD) simulations. Our results revealed that hCT_1-14 and hCT_26-32 predominantly existed as isolated monomers with transient small-sized oligomers, indicating weak aggregation tendencies. In contrast, hCT_15-25 exhibited robust aggregation capability, forming stable β-sheet aggregates independently. Full-length hCT_1-32 monomers displayed dynamic helical structures, with dimerization decreasing helix content and enhancing β-sheet formation. The transition to β-sheets in full-length hCT_1-32 correlated with the loss of helical structure in the hCT_15-25 region. Conformations with high helical content in hCT_15-25 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.

Keywords: Amyloid aggregation; Discrete molecular dynamics; Human calcitonin.