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.

Computational Investigation of Coaggregation and Cross-Seeding between Aβ and hIAPP Underpinning the Cross-Talk in Alzheimer's Disease and Type 2 Diabetes.

The coexistence of amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP) in the brain and pancreas is associated with an increased risk of Alzheimer's disease (AD) and type 2 diabetes (T2D) due to their coaggregation and cross-seeding. Despite this, the molecular mechanisms underlying their interaction remain elusive. Here, we systematically investigated the cross-talk between Aβ and hIAPP using atomistic discrete molecular dynamics (DMD) simulations.

Computational insights into the cross-talk between medin and Aβ: implications for age-related vascular risk factors in Alzheimer's disease.

The aggregation of medin forming aortic medial amyloid is linked to arterial wall degeneration and cerebrovascular dysfunction. Elevated levels of arteriolar medin are correlated with an increased presence of vascular amyloid-β (Aβ) aggregates, a hallmark of Alzheimer's disease (AD) and vascular dementia. The cross-interaction between medin and Aβ results in the formation of heterologous fibrils through co-aggregation and cross-seeding processes both in vitro and in vivo.

Deciphering the influence of Y12L and N17H substitutions on the conformation and oligomerization of human calcitonin.

The abnormal aggregation of human calcitonin (hCT) hormone peptides impairs their physiological function, leading to harmful immune responses and cytotoxicity, which limits their clinical utility. Interestingly, a representative hCT analog incorporating Y12L and N17H substitutions (DM-hCT) has shown reduced aggregation tendencies while maintaining bioactivity. But the molecular mechanism of Y12L and N17H substitutions on the conformational dynamics of hCT remains unclear.

Unveiling Medin Folding and Dimerization Dynamics and Conformations via Atomistic Discrete Molecular Dynamics Simulations.

Medin is a principal component of localized amyloid found in the vasculature of individuals over 50 years old. Its amyloid aggregation has been linked to endothelial dysfunction and vascular inflammation, contributing to the pathogenesis of various vascular diseases. Despite its significance, the structures of the medin monomer, oligomer, and fibril remain elusive, and the dynamic processes of medin aggregation are not fully understood.

SEVI Inhibits Aβ Amyloid Aggregation by Capping the β-Sheet Elongation Edges.

Inhibiting the aggregation of amyloid peptides with endogenous peptides has broad interest due to their intrinsically high biocompatibility and low immunogenicity. Here, we investigated the inhibition mechanism of the prostatic acidic phosphatase fragment SEVI (semen-derived enhancer of viral infection) against Aβ42 fibrillization using atomistic discrete molecular dynamic simulations. Our result revealed that SEVI was intrinsically disordered with dynamic formation of residual helices.