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講者：邱繼正教授
演講題目：Conformations of Amyloid Forming Pepetides
演講時間：12/12（五）15:30~17:00
演講地點：博雅館 103
主持人：呂宗昕教授
Conformations of Amyloid Forming Peptides
*Chi-cheng Chiu
Department of Chemical Engineering, National Cheng Kung University
Phone: 06-2757575 ext 62659, Fax : 06-2344496
*E-mail: ccchiu2@mail.ncku.edu.tw
The biological functions of proteins, or polypeptides, are largely determined by their unique three-dimensional structures, or folded states. Changes in physical or chemical properties of a protein or its surrounding environment can lead to protein misfolding and impair its biological function. Certain misfolded polypeptides can aggregate into ordered fibrillar morphologies rich in the β-sheet secondary structure, also known as amyloid. Amyloid formation is implicated in more than 20 human diseases, including Alzheimer’s disease, Parkinson’s disease, Creutzfeldt-Jakob disease, and type II diabetes (T2D), etc. Recent studies have suggested that the polypeptide oligomers, or the intermediate species in the early stage of the aggregation pathway, have the most cytotoxicity. Hence, understanding the forming mechanism of oligomers and the following aggregation of these amyloid polypeptides are critical to controlling their self-assembling behaviors and to developing the therapeutic strategies for the related diseases.
In the presented work, we focus on the folding and the oligomerization mechanisms of human islet amyloid polypeptide (hIAPP, or human amylin), a 37-residue hormone co-secreted with insulin by the pancreatic β-cells. Formation of hIAPP amyloid deposits is associated with the development of T2D. We combine molecular simulations with various advanced sampling techniques, such as metadynamics (MetaDyn) and transition path sampling (TPS), to study the monomer conformations and the oligomerization processes of hIAPP. Our results demonstrate that hIAPP can adopt a α-helical conformation, various b-sheet conformations, or unstructured coils. Detailed computational analysis illustrates the folding pathways between the various conformational states of hIAPP. We further characterize the conformational free energies of hIAPP amyloid dimer, illustrating the intermediate during the aggregation, which is further complement with experimental results. Effects of mutations on hIAPP monomer and amyloid dimer conformations are also examined. Our simulation results combined with experimental data provide valuable insights for the development of therapeutic inhibitors of hIAPP amyloid plaques.
Keywords: amyloid, hIAPP, free energy, aggregation pathway
Recent references:
(1) Middleton, C. T., Marek, P., Cao, P., Chiu, C.-C., Singh, S., Woys, A. M., et al. (2012). Two-dimensional infrared spectroscopy reveals the complex behaviour of an amyloid fibril inhibitor. Nat. Chem., 4(5), 355.
(2) Singh, S., Chiu, C.-C., Reddy, A. S., & de Pablo, J. J. (2013). α-helix to β-hairpin transition of human amylin monomer. J. Chem. Phys., 138(15), 155101.
(3) Chiu, C.-C., Singh, S., & de Pablo, J. J. (2013). Effect of Proline Mutations on the Monomer Conformations of Amylin. Biophys. J., 105(5), 1227.
(4) Buchanan, L. E., Dunkelberger, E. B., Tran, H. Q., Cheng, P.-N., Chiu, C.-C., Cao, P., et al. (2013). Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient β-sheet. Proc. Natl. Acad. Sci. U S A., 110(48), 19285.
關於本次演講資訊請參考附件檔案，謝謝。
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