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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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