Ma Buyong, Nussinov Ruth
Basic Research Program, SAIC-Frederick Inc, Center for Cancer Research, Nanobiology Program, NCI-Frederick, Frederick MD 21702, USA.
Curr Opin Chem Biol. 2006 Oct;10(5):445-52. doi: 10.1016/j.cbpa.2006.08.018. Epub 2006 Aug 28.
Computational tools are increasingly being applied to solve the protein aggregation problem, providing insight into amyloid structures and aggregation mechanisms. The paradigm of Abeta amyloid structure elucidation provides an example of an innovative experimental design and endeavor, echoing the computational testing of possible molecular associations, all reflected in the current Ma-Nussinov-Tycko model of the Abeta amyloid. Simulations have shown that dimer formation can lock some misfolded conformations, and catalyze the shift of the equilibrium away from the native state. In most cases, a stable amyloid seed requires at least two-layered beta-sheets with properly registered side-chains. Under kinetic control, the final protein aggregations are the outcome of maximizing the van der Waals interactions between side chains and backbone hydrogen bonds.
计算工具正越来越多地被用于解决蛋白质聚集问题，为深入了解淀粉样蛋白结构和聚集机制提供了帮助。β-淀粉样蛋白结构阐明的范例提供了一个创新实验设计与努力的例子，这与对可能的分子关联进行的计算测试相呼应，所有这些都反映在当前β-淀粉样蛋白的马-努西诺夫-泰科模型中。模拟表明，二聚体的形成可以锁定一些错误折叠的构象，并催化平衡从天然状态发生转变。在大多数情况下，一个稳定的淀粉样蛋白种子至少需要具有适当对齐侧链的两层β-折叠片层。在动力学控制下，最终的蛋白质聚集是侧链之间范德华相互作用和主链氢键最大化的结果。
