Protein misfolding and subsequent self-association are complex, intertwined processes, resulting in development of a heterogeneous population of aggregates closely related to many chronic pathological conditions including Type 2 Diabetes Mellitus and Alzheimer's disease. To address this issue, here, we develop a theoretical model in the general framework of linear stability analysis. According to this model, self-assemblies of peptides with pronounced conformational flexibility may become, under particular conditions, unstable and spontaneously evolve toward an alternating array of partially ordered and disordered monomers. The predictions of the theory were verified by atomistic molecular dynamics (MD) simulations of islet amyloid polypeptide (IAPP) used as a paradigm of aggregation-prone polypeptides (proteins). Simulations of dimeric, tetrameric, and hexameric human-IAPP self-assemblies at physiological electrolyte concentration reveal an alternating distribution of the smallest domains (of the order of the peptide mean length) formed by partially ordered (mainly β-strands) and disordered (turns and coil) arrays. Periodicity disappears upon weakening of the inter-peptide binding, a result in line with the predictions of the theory. To further probe the general validity of our hypothesis, we extended the simulations to other peptides, the Aβ(1-40) amyloid peptide, and the ovine prion peptide as well as to other proteins (SOD1 dimer) that do not belong to the broad class of intrinsically disordered proteins. In all cases, the oligomeric aggregates show an alternate distribution of partially ordered and disordered monomers. We also carried out Surface Enhanced Raman Scattering (SERS) measurements of hIAPP as an experimental validation of both the theory and in silico simulations.

中文翻译：

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蛋白质自组装早期阶段的对称性断裂过渡。

蛋白质错误折叠和随后的自我缔合是复杂的，相互交织的过程，导致形成了与许多慢性病理状况（包括2型糖尿病和阿尔茨海默氏病）密切相关的异质聚集体。为了解决这个问题，在这里，我们在线性稳定性分析的一般框架中开发了一个理论模型。根据该模型，在特定条件下，具有明显构象柔性的肽的自组装可能变得不稳定，并自发地演变为部分有序和无序的单体交替排列。胰岛淀粉样多肽（IAPP）的原子分子动力学（MD）模拟用作易于聚集的多肽（蛋白质）的范例，验证了该理论的预测。二聚体的模拟 在生理电解质浓度下的四聚体和六聚体人IAPP自组装揭示了由部分有序（主要是β链）和无序（匝和线圈）阵列形成的最小域（肽平均长度的数量级）的交替分布。当肽间结合减弱时，周期性消失，这与该理论的预测相符。为了进一步探究我们的假设的一般有效性，我们将模拟扩展到了其他肽，Aβ（1-40）淀粉样蛋白肽和绵羊ion病毒肽以及不属于广泛范围的其他蛋白（SOD1二聚体）一类内在无序的蛋白质。在所有情况下，低聚聚集体均显示出部分有序和无序单体的交替分布。