Explicit Solvent Molecular Dynamics Simulations of A尾 Peptide Interacting with Ibuprofen Ligands

详细信息    查看全文

• 作者：Christopher Lockhart ; Seongwon Kim ; Dmitri K. Klimov
• 刊名：The Journal of Physical Chemistry B
• 出版年：2012
• 出版时间：November 1, 2012
• 年：2012
• 卷：116
• 期：43
• 页码：12922-12932
• 全文大小：547K
• 年卷期：v.116,no.43(November 1, 2012)
• ISSN：1520-5207

文摘

Using all-atom explicit water model and replica exchange molecular dynamics, we study the interactions between A尾 monomer and nonsteroidal anti-inflammatory drug ibuprofen, which is known to reduce the risk of Alzheimer鈥檚 disease. Ibuprofen binding to A尾 is largely governed by hydrophobic effect, and its binding site in A尾 peptide is entirely composed of hydrophobic amino acids. Electrostatic interactions between negatively charged ibuprofen ligands and positively charged side chains make a relatively small contribution to binding. This outcome is explained by the competition of ligand鈥損eptide electrostatic interactions with intrapeptide salt bridges. Consistent with the experiments, the S-isomer of ibuprofen binds with stronger affinity to A尾 than the R-isomer. Conformational ensemble of A尾 monomer in ibuprofen solution reveals two structured regions, 19鈥?5 (R1) and 29鈥?5 (R2), composed of turn/helix and helix structure, respectively. The clustering technique and free energy analysis suggest that A尾 conformational ensemble is mainly determined by the formation of Asp23-Lys28 salt bridge and the hydrophobic interactions between R1 and R2. Control simulations of A尾 peptide in ligand-free water show that ibuprofen binding changes A尾 structure by promoting the formation of helix and Asp23-Lys28 salt bridge. Implications of our findings for A尾 amyloidogenesis are discussed.