ArticleBiochimica et biophysica acta. Molecular basis of disease2019
Nucleation of β-rich oligomers and β-barrels in the early aggregation of human islet amyloid polypeptide.
Article in Biochimica et biophysica acta. Molecular basis of disease, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 58 citations in OpenAlex.
- Parallel in-register contact propensity predicts the Amyloidogenicity of ADan and ABri in familial dementias.International journal of biological macromolecules · 2026Article
- Monomer binding modes of small molecules that modulate the kinetics of hIAPP amyloid formation.bioRxiv : the preprint server for biology · 2025Article
- Conformational Ensemble Dynamics of Intrinsically Disordered Full-Length α- and β-Synuclein Monomers.Journal of chemical information and modeling · 2025Article
- The Glycine-Rich Region as a Flexible Molecular Glue Promoting hPrPJournal of chemical information and modeling · 2025Article
- Computational exploration of the self-aggregation mechanisms of phenol-soluble modulins β1 and β2 in Staphylococcus aureus biofilms.Colloids and surfaces. B, Biointerfaces · 2025Article
- Computational insights into the aggregation mechanism of human calcitonin.International journal of biological macromolecules · 2025Article
- Computational insights into the aggregation mechanism and amyloidogenic core of aortic amyloid medin polypeptide.Colloids and surfaces. B, Biointerfaces · 2024Article
- Computational Investigation of Coaggregation and Cross-Seeding between Aβ and hIAPP Underpinning the Cross-Talk in Alzheimer's Disease and Type 2 Diabetes.Journal of chemical information and modeling · 2024Article
- Molecular Insights into the Effects of F16L and F19L Substitutions on the Conformation and Aggregation Dynamics of Human Calcitonin.Journal of chemical information and modeling · 2024Article
- Computational insights into the cross-talk between medin and Aβ: implications for age-related vascular risk factors in Alzheimer's disease.Briefings in bioinformatics · 2024Article
- Deciphering the influence of Y12L and N17H substitutions on the conformation and oligomerization of human calcitonin.Soft matter · 2024Article
- Co-aggregation of α-synuclein with amyloid-β stabilizes β-sheet-rich oligomers and enhances the formation of β-barrels.Physical chemistry chemical physics : PCCP · 2023Article
- Nucleation and Growth of Amyloid Fibrils.The journal of physical chemistry. B · 2023Article
- Efficient optical plasmonic tweezer-controlled single-molecule SERS characterization of pH-dependent amylin species in aqueous milieus.Nature communications · 2023Article
- Unveiling Medin Folding and Dimerization Dynamics and Conformations via Atomistic Discrete Molecular Dynamics Simulations.Journal of chemical information and modeling · 2023Article
- SEVI Inhibits Aβ Amyloid Aggregation by Capping the β-Sheet Elongation Edges.Journal of chemical information and modeling · 2023Article
- Structural Perturbation of Monomers Determines the Amyloid Aggregation Propensity of Calcitonin Variants.Journal of chemical information and modeling · 2023Article
- Molecular Insights into the Misfolding and Dimerization Dynamics of the Full-Length α-Synuclein from Atomistic Discrete Molecular Dynamics Simulations.ACS chemical neuroscience · 2022Article
- Molecular insights into the oligomerization dynamics and conformations of amyloidogenic and non-amyloidogenic amylin from discrete molecular dynamics simulations.Physical chemistry chemical physics : PCCP · 2022Article
- Human islet amyloid polypeptide: A therapeutic target for the management of type 2 diabetes mellitus.Journal of pharmaceutical analysis · 2022Review
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
Abstract
The self-assembly of human islet amyloid polypeptide (hIAPP) into β-sheet rich amyloid aggregates is associated with pancreatic β-cell death in type 2 diabetes (T2D). Prior experimental studies of hIAPP aggregation reported the early accumulation of α-helical intermediates before the rapid conversion into β-sheet rich amyloid fibrils, as also corroborated by our experimental characterizations with transmission electron microscopy and Fourier transform infrared spectroscopy. Although increasing evidence suggests that small oligomers populating early hIAPP aggregation play crucial roles in cytotoxicity, structures of these oligomer intermediates and their conformational conversions remain unknown, hindering our understanding of T2D disease mechanism and therapeutic design targeting these early aggregation species. We further applied large-scale discrete molecule dynamics simulations to investigate the oligomerization of full-length hIAPP, employing multiple molecular systems of increasing number of peptides. We found that the oligomerization process was dynamic, involving frequent inter-oligomeric exchanges. On average, oligomers had more α-helices than β-sheets, consistent with ensemble-based experimental measurements. However, in ~4-6% independent simulations, β-rich oligomers expected as the fibrillization intermediates were observed, especially in the pentamer and hexamer simulations. These β-rich oligomers could adopt β-barrel conformations, recently postulated to be the toxic oligomer species but only observed computationally in the aggregates of short amyloid protein fragments. Free-energy analysis revealed high energies of these β-rich oligomers, supporting the nucleated conformational changes of oligomers in amyloid aggregation. β-barrel oligomers of full-length hIAPP with well-defined three-dimensional structures may play an important pathological role in T2D etiology and may be a therapeutic target for the disease.
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