Transthyretin (TTR) is a tetrameric homologous protein that can dissociate into monomers. Misfolding and aggregation of TTR can lead to amyloid transthyretin amyloidosis (ATTR), which can cause many diseases (e.g., senile systemic amyloidosis, familial amyloid cardiomyopathy, and familial amyloid polyneuropathy). Despite growing evidence indicating that small oligomers play a critical role in regulating cytotoxicity, the structures of these oligomeric intermediates and their conformational transformations are still unclear, impeding our understanding of neurodegenerative mechanisms and the development of therapeutics targeting early aggregation species. The TTR monomer protein consists of various fragments prone to self-aggregation, including the residue 105–115 sequence. Therefore, our study investigated the assembly progress of ATTR (105–115) peptides using all-atom molecular dynamics simulations. The findings indicate that the probability of β-sheet content increases with increasing numbers of peptides. Additionally, interactions between hydrophobic residues L110 and L111 are crucial for the formation of a β-rich oligomer formation. These β-rich oligomers may adopt β-barrel conformations, potentially toxic oligomer species. Free-energy analysis reveals that β-barrel conformations serve as intermediates for these β-rich oligomers. Our insights into the structural ensemble dynamics of ATTR (105–115) contribute to understanding the physical mechanisms underlying the β-barrel oligomers of ATTR. These findings may shed light on the pathological role of ATTR in neurodegenerative diseases and offer potential therapeutic targets.

中文翻译：

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ATTR (105–115) 组装的富含 β 低聚物的结构和动力学

甲状腺素运载蛋白 (TTR) 是一种四聚体同源蛋白，可以解离成单体。 TTR的错误折叠和聚集可导致淀粉样转甲状腺素蛋白淀粉样变性(ATTR)，从而引起多种疾病(如老年系统性淀粉样变性、家族性淀粉样心肌病和家族性淀粉样多发性神经病)。尽管越来越多的证据表明小寡聚体在调节细胞毒性中发挥着关键作用，但这些寡聚中间体的结构及其构象转变仍不清楚，这阻碍了我们对神经退行性机制的理解和针对早期聚集物种的治疗方法的开发。 TTR 单体蛋白由各种易于自聚集的片段组成，包括残基 105-115 序列。因此，我们的研究利用全原子分子动力学模拟研究了 ATTR (105–115) 肽的组装进展。研究结果表明，β-折叠含量的可能性随着肽数量的增加而增加。此外，疏水残基 L110 和 L111 之间的相互作用对于形成富含 β 的寡聚物至关重要。这些富含β的寡聚物可能采用β-桶构象，具有潜在毒性的寡聚物种类。自由能分析表明，β-桶构象是这些富含 β 的寡聚物的中间体。我们对 ATTR (105-115) 结构系综动力学的深入了解有助于理解 ATTR β 桶低聚物背后的物理机制。这些发现可能揭示 ATTR 在神经退行性疾病中的病理作用，并提供潜在的治疗靶点。