Nguyen Phuong H, Li Mai Suan, Stock Gerhard, Straub John E, Thirumalai D
*Institute of Physical and Theoretical Chemistry, J. W. Goethe University, Marie-Curie-Strasse 11, D-60439 Frankfurt, Germany.
Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):111-6. doi: 10.1073/pnas.0607440104. Epub 2006 Dec 26.
Nonfibrillar soluble oligomers, which are intermediates in the transition from monomers to amyloid fibrils, may be the toxic species in Alzheimer's disease. To monitor the early events that direct assembly of amyloidogenic peptides we probe the dynamics of formation of (Abeta(16-22))(n) by adding a monomer to a preformed (Abeta(16-22))(n-1) (n = 4-6) oligomer in which the peptides are arranged in an antiparallel beta-sheet conformation. All atom molecular dynamics simulations in water and multiple long trajectories, for a cumulative time of 6.9 mus, show that the oligomer grows by a two-stage dock-lock mechanism. The largest conformational change in the added disordered monomer occurs during the rapid ( approximately 50 ns) first dock stage in which the beta-strand content of the monomer increases substantially from a low initial value. In the second slow-lock phase, the monomer rearranges to form in register antiparallel structures. Surprisingly, the mobile structured oligomers undergo large conformational changes in order to accommodate the added monomer. The time needed to incorporate the monomer into the fluid-like oligomer grows even when n = 6, which suggests that the critical nucleus size must exceed six. Stable antiparallel structure formation exceeds hundreds of nanoseconds even though frequent interpeptide collisions occur at elevated monomer concentrations used in the simulations. The dock-lock mechanism should be a generic mechanism for growth of oligomers of amyloidogenic peptides.
非纤维状可溶性寡聚体是单体向淀粉样纤维转变过程中的中间体，可能是阿尔茨海默病中的毒性物质。为了监测指导淀粉样生成肽组装的早期事件，我们通过将一个单体添加到预先形成的（Abeta(16 - 22))(n - 1)（n = 4 - 6）寡聚体中来探测（Abeta(16 - 22))(n)的形成动力学，其中肽以反平行β-折叠构象排列。在水中进行的全原子分子动力学模拟以及多条长时间轨迹，累计时间为6.9微秒，结果表明寡聚体通过两阶段对接-锁定机制生长。添加的无序单体中最大的构象变化发生在快速（约50纳秒）的第一对接阶段，在此阶段单体的β-链含量从低初始值大幅增加。在第二缓慢锁定阶段，单体重新排列形成对齐的反平行结构。令人惊讶的是，可移动的结构化寡聚体会发生大的构象变化以容纳添加的单体。即使n = 6时，将单体纳入类流体寡聚体所需的时间也会增加，这表明临界核尺寸必须超过六个。尽管在模拟中使用的较高单体浓度下肽间频繁碰撞，但稳定的反平行结构形成仍超过数百纳秒。对接-锁定机制应该是淀粉样生成肽寡聚体生长的一种通用机制。
