Pathological aggregation of essentially dissociated Transthyretin (TTR) monomer proteins, driven by misfolding and self-interaction, is associated with Transthyretin amyloidosis (ATTR) disease. The TTR monomer proteins consist of several fragments that tend to self-aggregate. Recent experimental studies showed that the sequence of residues TTR_91–96 plays an important role in self-aggregation. However, the mechanisms underlying the misfolding and aggregation of the TTR_91–96 monomers are still unknown. In this study, we used microsecond molecular dynamics simulations to investigate the misfolding and self-assembly of TTR_91–96 Octamers. We also investigated E92P and V94P mutants for comparative analysis. The analysis indicates that hydrophobic interactions and π–π stacking patterns play important roles in reducing the β-sheet content in the V94P and E92P mutants. Additionally, our findings reveal the conformational transition of TTR_91–96 octamer from closed β-barrel, open β-barrel to the β-bilayer aggregation. We further elucidate the dynamic mechanism of the transition from intermediate states to stable states. Overall, our research may contribute to the development of drug design to combat fibrous amyloid fibrous diseases.

中文翻译：

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具有脯氨酸突变的 TTR91-96 构象转变的物理驱动力


由错误折叠和自身相互作用驱动的基本解离的转甲状腺素蛋白 （TTR） 单体蛋白的病理聚集与转甲状腺素蛋白淀粉样变性 （ATTR） 疾病有关。TTR 单体蛋白由几个倾向于自聚集的片段组成。最近的实验研究表明，残基序列 TTR_91-96 在自聚集中起重要作用。然而，TTR_91-96 单体错误折叠和聚集的机制仍然未知。在这项研究中，我们使用微秒分子动力学模拟来研究 TTR_91-96 八聚体的错误折叠和自组装。我们还研究了 E92P 和 V94P 突变体进行比较分析。分析表明，疏水相互作用和 π-π 堆叠模式在降低 V94P 和 E92P 突变体中的 β 片含量方面起着重要作用。此外，我们的研究结果揭示了 TTR_91-96 八聚体从封闭的 β 桶、开放的 β 桶到 β 双层聚集的构象转变。我们进一步阐明了从中间态到稳定态转变的动态机制。总体而言，我们的研究可能有助于开发对抗纤维淀粉样蛋白纤维病的药物设计。