Alzheimer鈥檚 A尾10鈥?0 Peptide Binds and Penetrates DMPC Bilayer: An Isobaric鈥揑sothermal Replica Exchange Molecular Dynamics Study

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• 作者：Christopher Lockhart ; Dmitri K. Klimov
• 刊名：Journal of Physical Chemistry B
• 出版年：2014
• 出版时间：March 13, 2014
• 年：2014
• 卷：118
• 期：10
• 页码：2638-2648
• 全文大小：585K
• 年卷期：v.118,no.10(March 13, 2014)
• ISSN：1520-5207

文摘

Using all-atom explicit solvent model and isobaric鈥搃sothermal replica exchange molecular dynamics, we studied binding of A尾10鈥?0 monomers to zwitterionic DMPC bilayer. Our simulations suggest three main conclusions. First, binding of A尾10鈥?0 monomer to the DMPC bilayer causes dramatic structural transition in the peptide resulting in the formation of stable helical structure in the C-terminal. In addition, binding to the lipid bilayer induces the formation of intrapeptide Asp23-Lys28 salt bridge. We argue that the emergence of helix is the consequence of hidden helix propensity harbored in the A尾10鈥?0 C-terminal. This propensity is revealed by the lipids cross-bridging amino acids in helical conformations and by significant hydrophobic moment of the C-terminal. Second, the central hydrophobic cluster and, particularly, the C-terminal of A尾10鈥?0 not only govern binding to the bilayer but also penetrate into bilayer core. In contrast, the polar N-terminal and turn region form interactions mainly with the bilayer surface. Third, our simulations suggest that upon A尾10鈥?0 binding to the bilayer a highly heterogeneous local environment emerges along A尾10鈥?0 chain. The N-terminal is exposed to polar well-hydrated medium, whereas the C-terminal is largely shielded from water residing in mostly hydrophobic environment. The implication of our results is that A尾 aggregation mediated by zwitterionic lipid bilayer is likely to be different from that in bulk water.