Zheng Jie, Jang Hyunbum, Ma Buyong, Nussinov Ruth
Department of Chemical and Biomolecular Engineering, The University of Akron, Akron, Ohio 44325, USA.
J Phys Chem B. 2008 Jun 5;112(22):6856-65. doi: 10.1021/jp711335b. Epub 2008 May 6.
We report all-atom molecular dynamics simulations of annular beta-amyloid (17-42) structures, single- and double-layered, in solution. We assess the structural stability and association force of Abeta annular oligomers associated through different interfaces, with a mutated sequence (M35A), and with the oxidation state (M35O). Simulation results show that single-layered annular models display inherent structural instability: one is broken down into linear-like oligomers, and the other collapses. On the other hand, a double-layered annular structure where the two layers interact through their C-termini to form an NC-CN interface (where N and C are the N and C termini, respectively) exhibits high structural stability over the simulation time due to strong hydrophobic interactions and geometrical constraints induced by the closed circular shape. The observed dimensions and molecular weight of the oligomers from atomic force microscopy (AFM) experiments are found to correspond well to our stable double-layered model with the NC-CN interface. Comparison with K3 annular structures derived from the beta 2-microglobulin suggests that the driving force for amyloid formation is sequence specific, strongly dependent on side-chain packing arrangements, structural morphologies, sequence composition, and residue positions. Combined with our previous simulations of linear-like Abeta, K3 peptide, and sup35-derived GNNQQNY peptide, the annular structures provide useful insight into oligomeric structures and driving forces that are critical in amyloid fibril formation.
我们报告了溶液中单层和双层环状β-淀粉样蛋白（17-42）结构的全原子分子动力学模拟。我们评估了通过不同界面结合的β-淀粉样蛋白环状寡聚体、具有突变序列（M35A）的寡聚体以及具有氧化态（M35O）的寡聚体的结构稳定性和结合力。模拟结果表明，单层环状模型表现出固有的结构不稳定性：一种分解为线性样寡聚体，另一种则坍塌。另一方面，双层环状结构中两层通过其C端相互作用形成NC-CN界面（其中N和C分别为N端和C端），由于封闭圆形形状引起的强疏水相互作用和几何约束，在模拟时间内表现出高结构稳定性。原子力显微镜（AFM）实验中观察到的寡聚体尺寸和分子量与我们具有NC-CN界面的稳定双层模型非常吻合。与源自β2-微球蛋白的K3环状结构的比较表明，淀粉样蛋白形成的驱动力具有序列特异性，强烈依赖于侧链堆积排列、结构形态、序列组成和残基位置。结合我们之前对线性样β-淀粉样蛋白、K3肽和源自sup35的GNNQQNY肽的模拟，环状结构为寡聚体结构和淀粉样纤维形成中关键的驱动力提供了有用的见解。
