Zheng Jie, Jang Hyunbum, Ma Buyong, Tsai Chung-Jun, Nussinov Ruth
Basic Research Program, SAIC-Frederick Center for Cancer Research, Nanobiology Program, NCI-Frederick, Frederick, Maryland 21702, USA.
Biophys J. 2007 Nov 1;93(9):3046-57. doi: 10.1529/biophysj.107.110700. Epub 2007 Aug 3.
We investigate Abeta(17-42) protofibril structures in solution using molecular dynamics simulations. Recently, NMR and computations modeled the Abeta protofibril as a longitudinal stack of U-shaped molecules, creating an in-parallel beta-sheet and loop spine. Here we study the molecular architecture of the fibril formed by spine-spine association. We model in-register intermolecular beta-sheet-beta-sheet associations and study the consequences of Alzheimer's mutations (E22G, E22Q, E22K, and M35A) on the organization. We assess the structural stability and association force of Abeta oligomers with different sheet-sheet interfaces. Double-layered oligomers associating through the C-terminal-C-terminal interface are energetically more favorable than those with the N-terminal-N-terminal interface, although both interfaces exhibit high structural stability. The C-terminal-C-terminal interface is essentially stabilized by hydrophobic and van der Waals (shape complementarity via M35-M35 contacts) intermolecular interactions, whereas the N-terminal-N-terminal interface is stabilized by hydrophobic and electrostatic interactions. Hence, shape complementarity, or the "steric zipper" motif plays an important role in amyloid formation. On the other hand, the intramolecular Abeta beta-strand-loop-beta-strand U-shaped motif creates a hydrophobic cavity with a diameter of 6-7 A, allowing water molecules and ions to conduct through. The hydrated hydrophobic cavities may allow optimization of the sheet association and constitute a typical feature of fibrils, in addition to the tight sheet-sheet association. Thus, we propose that Abeta fiber architecture consists of alternating layers of tight packing and hydrated cavities running along the fibrillar axis, which might be possibly detected by high-resolution imaging.
我们使用分子动力学模拟研究溶液中的β淀粉样蛋白（17 - 42）原纤维结构。最近，核磁共振（NMR）和计算研究将β淀粉样蛋白原纤维模拟为U形分子的纵向堆叠，形成平行β折叠片层和环脊。在此，我们研究由脊 - 脊缔合形成的原纤维的分子结构。我们模拟了分子间β折叠片层 - β折叠片层的对齐缔合，并研究了阿尔茨海默病突变（E22G、E22Q、E22K和M35A）对其结构的影响。我们评估了具有不同片层 - 片层界面的β淀粉样蛋白寡聚体的结构稳定性和缔合力。通过C末端 - C末端界面缔合的双层寡聚体在能量上比通过N末端 - N末端界面缔合的更为有利，尽管这两种界面都表现出较高的结构稳定性。C末端 - C末端界面主要通过疏水和范德华力（通过M35 - M35接触实现形状互补）分子间相互作用得以稳定，而N末端 - N末端界面则通过疏水和静电相互作用得以稳定。因此，形状互补，即“空间拉链”基序在淀粉样蛋白形成中起着重要作用。另一方面，分子内的β淀粉样蛋白β链 - 环 - β链U形基序形成了一个直径为6 - 7埃的疏水腔，允许水分子和离子通过。水合疏水腔可能有助于优化片层缔合，并且除了紧密的片层 - 片层缔合外，还构成了原纤维的一个典型特征。因此，我们提出β淀粉样蛋白纤维结构由沿纤维轴交替排列的紧密堆积层和水合腔组成，这可能通过高分辨率成像检测到。
