Zheng Jie, Ma Buyong, Chang Yung, Nussinov Ruth
Department of Chemical and Biomolecular Engineering, The University of Akron, Akron, Ohio 44325, USA.
Front Biosci. 2008 May 1;13:3919-30. doi: 10.2741/2980.
Amyloid-beta (Abeta) peptides can elongate in the fibril axis and associate in the lateral direction. We present detailed atomic Abeta models with different in-register intermolecular beta-sheet-beta-sheet associations. We probe structural stability, conformational dynamics, and association force of Abeta oligomers with various sizes and structures for both wild-type and mutated sequences using molecular dynamics (MD) simulations. MD simulations show that an Abeta oligomer that is laterally associated through the C-terminal-C-terminal interface is energetically more favorable than other oligomers with the N-terminal-N-terminal and C-terminal-N-terminal interfaces. We further develop a simple numerical model to describe the kinetics of Abeta aggregation process by considering fibril elongation and lateral association using a Monte Carlo algorithm. Kinetic data suggest that fibril elongation and lateral association are mutually competitive. Single-point mutations of Glu22 or Met35 at the interfaces have profound negative effects on intermolecular beta-sheet-beta-sheet association. These disease-related mutants (E22K, E22Q, and M35O) display more flexible structures, weaker lateral association, and stronger elongation tendencies than the wild type, suggesting that amyloid oligomerization and neurotoxicity might be linked to fibril longitudinal growth.
β淀粉样蛋白（Aβ）肽可沿纤维轴伸长并在横向缔合。我们展示了具有不同共线分子间β折叠-β折叠缔合的详细原子Aβ模型。我们使用分子动力学（MD）模拟探究了野生型和突变序列中各种大小和结构的Aβ寡聚体的结构稳定性、构象动力学和缔合力。MD模拟表明，通过C端-C端界面横向缔合的Aβ寡聚体在能量上比具有N端-N端和C端-N端界面的其他寡聚体更有利。我们进一步开发了一个简单的数值模型，通过使用蒙特卡罗算法考虑纤维伸长和横向缔合来描述Aβ聚集过程的动力学。动力学数据表明纤维伸长和横向缔合相互竞争。界面处Glu22或Met35的单点突变对分子间β折叠-β折叠缔合有深远的负面影响。这些与疾病相关的突变体（E22K、E22Q和M35O）比野生型显示出更灵活的结构、更弱的横向缔合和更强的伸长趋势，表明淀粉样寡聚化和神经毒性可能与纤维纵向生长有关。
