School of Systems Biology, George Mason University, Manassas, Virginia 20110, United States.
J Phys Chem B. 2012 Nov 1;116(43):12922-32. doi: 10.1021/jp306208n. Epub 2012 Oct 18.
Using all-atom explicit water model and replica exchange molecular dynamics, we study the interactions between Aβ monomer and nonsteroidal anti-inflammatory drug ibuprofen, which is known to reduce the risk of Alzheimer's disease. Ibuprofen binding to Aβ is largely governed by hydrophobic effect, and its binding site in Aβ 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-peptide electrostatic interactions with intrapeptide salt bridges. Consistent with the experiments, the S-isomer of ibuprofen binds with stronger affinity to Aβ than the R-isomer. Conformational ensemble of Aβ monomer in ibuprofen solution reveals two structured regions, 19-25 (R1) and 29-35 (R2), composed of turn/helix and helix structure, respectively. The clustering technique and free energy analysis suggest that Aβ conformational ensemble is mainly determined by the formation of Asp23-Lys28 salt bridge and the hydrophobic interactions between R1 and R2. Control simulations of Aβ peptide in ligand-free water show that ibuprofen binding changes Aβ structure by promoting the formation of helix and Asp23-Lys28 salt bridge. Implications of our findings for Aβ amyloidogenesis are discussed.
利用全原子显式水分子模型和复制交换分子动力学，我们研究了 Aβ 单体与非甾体抗炎药布洛芬之间的相互作用，已知布洛芬可降低阿尔茨海默病的风险。布洛芬与 Aβ 的结合主要受疏水性影响，其在 Aβ 肽中的结合位点完全由疏水性氨基酸组成。带负电荷的布洛芬配体与带正电荷的侧链之间的静电相互作用对结合的贡献相对较小。这一结果可以通过配体-肽静电相互作用与肽内盐桥的竞争来解释。与实验一致，布洛芬的 S-异构体比 R-异构体与 Aβ 的结合亲和力更强。在布洛芬溶液中 Aβ 单体的构象集合揭示了两个结构区域，19-25（R1）和 29-35（R2），分别由转角/螺旋和螺旋结构组成。聚类技术和自由能分析表明，Aβ 构象集合主要由 Asp23-Lys28 盐桥的形成和 R1 与 R2 之间的疏水性相互作用决定。在无配体水的 Aβ 肽的对照模拟中，布洛芬的结合通过促进螺旋和 Asp23-Lys28 盐桥的形成来改变 Aβ 的结构。我们的发现对 Aβ 淀粉样蛋白形成的意义进行了讨论。
