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Molecular dynamics simulations reveal the disruption mechanism of a 2,4-thiazolidinedione derivative C30 against tau hexapeptide (PHF6) oligomer
Proteins: Structure, Function, and Bioinformatics ( IF 2.9 ) Pub Date : 2021-07-30 , DOI: 10.1002/prot.26196
Hongli Liu 1, 2 , Haiyang Zhong 3 , Huanxiang Liu 2 , Xiaojun Yao 3, 4
Affiliation  

Derivatives of 2,4-thiazolidinedione have been reported to inhibit the aggregation of tau protein, in which compound 30 (C30) not only inhibit 80% of paired helical filament 6 (PHF6) aggregation, but also inhibit K18 and full-length tau aggregation. However, its inhibitory mechanism is unclear. In this study, to investigate the effect of C30 on tau protein, all-atom molecular dynamics simulation was performed on the PHF6 oligomer with and without C30. The results show that C30 can cause significant conformational changes in the PHF6 oligomer. The nematic order parameter P2 and secondary structure analyses show that C30 destroys the ordered structure of PHF6 oligomer, reduces the content of β-sheet structure, and transforms β-sheet into random coil structure. By clustering analysis, it was found that C30 has four possible binding sites on the PFH6 oligomer, and the binding ability order is S1 > S2 > S4 > S3. Following a more in-depth analyses of each site, it was determined that the S1 site is the most possible binding site mainly located between layers of L1 and L3. The hydrophobic interaction is the driving force for the binding of C30 to PHF6 oligomer. In addition, L1P4_Y310, L1P5_Y310, L3P1_V309, and L3P2_V309 are key residues for C30 binding to oligomer. Moreover, π-π interaction formed by L1P4_Y310 and L1P5_Y310 with C30 and the hydrogen bonding interaction formed by C30 with L3P3_Q307 are beneficial to the combination of C30 and oligomer. The fully understanding disrupt the mechanism of 2,4-thiazolidinedione derivative on PHF6 oligomer and the identification of binding sites will help design and discover new AD inhibitors in the future.

中文翻译:

分子动力学模拟揭示了 2,4-噻唑烷二酮衍生物 C30 对 tau 六肽 (PHF6) 寡聚体的破坏机制

据报道,2,4-噻唑烷二酮的衍生物可抑制 tau 蛋白的聚集,其中化合物 30 (C30) 不仅能抑制 80% 的成对螺旋丝 6 (PHF6) 聚集,还能抑制 K18 和全长 tau 聚集. 但其抑制机制尚不清楚。在本研究中,为了研究 C30 对 tau 蛋白的影响,对含有和不含 C30 的 PHF6 寡聚体进行了全原子分子动力学模拟。结果表明,C30 可以引起 PHF6 寡聚体的显着构象变化。向列有序参数P2和二级结构分析表明,C30破坏了PHF6低聚物的有序结构,降低了β-折叠结构的含量,使β-折叠转变为无规卷曲结构。通过聚类分析,发现C30在PFH6寡聚体上有四个可能的结合位点,结合能力顺序为S1>S2>S4>S3。在对每个位点进行更深入的分析后,确定 S1 位点是最可能的结合位点,主要位于层之间L 1 和L 3。疏水相互作用是C30 与PHF6 低聚物结合的驱动力。此外,L 1 P 4_Y310、L 1 P 5_Y310、L 3 P 1_V309 和L 3 P 2_V309 是C30 与寡聚体结合的关键残基。此外,L 1 P 4_Y310 和L 1 P 5_Y310 与C30形成的π-π 相互作用以及C30 与L 3 P形成的氢键相互作用3_Q307有利于C30与低聚物的结合。充分理解2,4-噻唑烷二酮衍生物在PHF6寡聚体上的作用机制,结合位点的鉴定将有助于未来设计和发现新的AD抑制剂。
更新日期:2021-07-30
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