Structures of the Alzheimer鈥檚 Wild-Type A尾1-40 Dimer from Atomistic Simulations
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- 作者：Bogdan Tarus ; Thanh T. Tran ; Jessica Nasica-Labouze ; Fabio Sterpone ; Phuong H. Nguyen ; Philippe Derreumaux
- 刊名：Journal of Physical Chemistry B
- 出版年：2015
- 出版时间：August 20, 2015
- 年：2015
- 卷：119
- 期：33
- 页码：10478-10487
- 全文大小：634K
- ISSN：1520-5207
文摘
We have studied the dimer of amyloid beta peptide A尾 of 40 residues by means of all-atom replica exchange molecular dynamics. The A尾-dimers have been found to be the smallest toxic species in Alzheimer鈥檚 disease, but their inherent flexibilities have precluded structural characterization by experimental methods. Though the 24-渭s-scale simulation reveals a mean secondary structure of 18% 尾-strand and 10% 伪 helix, we find transient configurations with an unstructured N-terminus and multiple 尾-hairpins spanning residues 17鈥?1 and 30鈥?6, but the antiparallel and perpendicular peptide orientations are preferred over the parallel organization. Short-lived conformational states also consist of all 伪 topologies, and one compact peptide with 尾-sheet structure stabilized by a rather extended peptide with 伪-helical content. Overall, this first all-atom study provides insights into the equilibrium structure of the A尾1-40 dimer in aqueous solution, opening a new avenue for a comprehensive understanding of the impact of pathogenic and protective mutations in early-stage Alzheimer鈥檚 disease on a molecular level.