Characterization of the nucleation barriers for protein aggregation and amyloid formation
Characterization of the nucleation barriers for protein aggregation and amyloid formation
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DOI：
10.2976/1.2760023
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发表时间：
2007-07-01
期刊：
影响因子：
--
通讯作者：
Vendruscolo, Michele
中科院分区：
文献类型：
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作者：
Auer, Stefan;Dobson, Christopher M.;Vendruscolo, Michele
尽管氨基酸密码复杂且特异，但序列和功能无关的多种肽和蛋白质表现出共同的行为并组装成高度组织化的淀粉样蛋白原纤维。这种聚集体的形成通常通过成核和生长机制来描述，其中所涉及的蛋白质在重组并生长成具有特征性交叉β结构的有序原纤维之前也形成中间低聚物聚集体。由于低聚物前体的瞬态性质和结构异质性，通过实验获得对这种现象的早期阶段的准确描述是极其困难的。在这里，我们调查的现象，有序聚集使用最近推出的管模型的多肽链与淀粉样蛋白形成的一般假设。在低聚物形成是罕见事件的条件下-通过实验形成淀粉样蛋白原纤维的最常见条件-我们直接计算与低聚物形成和转化为交叉β结构相关的成核屏障，以揭示这些物质的性质，确定临界核，并表征它们对肽的疏水性和与聚集和淀粉样蛋白形成相关的热力学参数的依赖性。
Despite the complexity and the specificity of the amino acid code, a variety of peptides and proteins unrelated in sequence and function exhibit a common behavior and assemble into highly organized amyloid fibrils. The formation of such aggregates is often described by a nucleation and growth mechanism, in which the proteins involved also form intermediate oligomeric aggregates before they reorganize and grow into ordered fibrils with a characteristic cross-beta structure. It is extremely difficult to experimentally obtain an accurate description of the early stages of this phenomenon due to the transient nature and structural heterogeneity of the oligomeric precursors. We investigate here the phenomenon of ordered aggregation by using the recently introduced tube model of polypeptide chains in conjunction with the generic hypothesis of amyloid formation. Under conditions where oligomer formation is a rare event-the most common conditions for forming amyloid fibrils by experiment-we calculate directly the nucleation barriers associated with oligomer formation and conversion into cross-beta structure in order to reveal the nature of these species, determine the critical nuclei, and characterize their dependence on the hydrophobicity of the peptides and the thermodynamic parameters associated with aggregation and amyloid formation.