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Molecular Dynamics Study of Structure, Folding and Aggregation of Poly-Proline-Arginine (Poly-PR) and Poly-Glycine-Arginine (Poly-GR) Proteins
Biophysical Journal ( IF 3.4 ) Pub Date : 2021-01-01 , DOI: 10.1016/j.bpj.2020.11.2258
Size Zheng 1 , Ali Sahimi 2 , Katherine S Shing 3 , Muhammad Sahimi 3
Affiliation  

Poly-proline-arginine (poly-PR) and poly-glycine-arginine (poly-GR) proteins are believed to the most toxic dipeptide repeat (DPR) proteins that are expressed by the hexanucleotide repeat expansion mutation in C9ORF72, which are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) diseases. Their structural information and mechanisms of toxicity remain incomplete, however. Using molecular dynamics simulation and all-atom model of proteins, we study folding and aggregation of both poly-PR and poly-GR. The results indicate formation of double-helix structure during the aggregation of poly-PR into dimers, whereas no stable aggregate is formed during the aggregation of poly-GR; the latter only folds into α-helix and double-helix structures that are similar to those formed in the folding of poly-glycine-alanine (poly-GA) protein. Our findings are consistent with the experimental data indicating that poly-PR and poly-GR are less likely to aggregate, due to the hydrophilic arginine residues within their structures. Such characteristics could, however, in some respect facilitate migration of the DPR proteins between and within cells, and at the same time, give proline residues the benefits of activating the receptors that regulate ionotropic effect in neurons, resulting in death or malfunction of neurons due to the abnormal increase or decrease of the ion transmission. This may explain the neurotoxicities of poly-PR and poly-GR associated with many neurodegenerative diseases. To our knowledge, this is the first molecular dynamics simulation of the phenomena involving poly-PR and poly-GR proteins.

中文翻译:

聚脯氨酸精氨酸 (Poly-PR) 和聚甘氨酸精氨酸 (Poly-GR) 蛋白的结构、折叠和聚集的分子动力学研究

聚脯氨酸精氨酸 (poly-PR) 和聚甘氨酸精氨酸 (poly-GR) 蛋白被认为是毒性最强的二肽重复 (DPR) 蛋白,由 C9ORF72 中的六核苷酸重复扩增突变表达,与肌萎缩侧索硬化症(ALS)和额颞叶痴呆(FTD)疾病。然而,它们的结构信息和毒性机制仍然不完整。利用蛋白质的分子动力学模拟和全原子模型,我们研究了 poly-PR 和 poly-GR 的折叠和聚集。结果表明poly-PR聚合成二聚体时形成双螺旋结构,而poly-GR聚合过程中没有形成稳定的聚集体;后者仅折叠成类似于聚甘氨酸丙氨酸(poly-GA)蛋白折叠中形成的α-螺旋和双螺旋结构。我们的研究结果与实验数据一致,表明 poly-PR 和 poly-GR 不太可能聚集,因为它们的结构中存在亲水性精氨酸残基。然而,这些特性在某些方面可以促进 DPR 蛋白在细胞之间和细胞内的迁移,同时使脯氨酸残基具有激活调节神经元中离子型效应的受体的好处,从而导致神经元死亡或功能障碍。离子传输的异常增加或减少。这可以解释与许多神经退行性疾病相关的 poly-PR 和 poly-GR 的神经毒性。据我们所知,
更新日期:2021-01-01
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