Molecular dynamics simulations reveal the disruption mechanism of a 2,4‐thiazolidinedione derivative C30 against tau hexapeptide (PHF6) oligomer
Molecular dynamics simulations reveal the disruption mechanism of a 2,4‐thiazolidinedione derivative C30 against tau hexapeptide (PHF6) oligomer
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DOI：
10.1002/prot.26196
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发表时间：
2021-07
期刊：
影响因子：
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通讯作者：
Hongli Liu;Haiyang Zhong;Huanxiang Liu;Xiaojun Yao
中科院分区：
文献类型：
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作者：
Hongli Liu;Haiyang Zhong;Huanxiang Liu;Xiaojun Yao
已经报道了2，4-噻唑烷二酮的衍生物抑制tau蛋白的聚集，其中化合物30（C30）不仅抑制80%的成对螺旋丝6（PHF 6）聚集，而且抑制K18和全长tau聚集。然而，其抑制机制尚不清楚。在这项研究中，为了研究C30对tau蛋白的影响，对含有和不含C30的PHF 6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PHF 6寡聚体的构象变化。P2和二级结构分析表明，C30破坏了PHF 6齐聚物的有序结构，减少了β-折叠结构的含量，使β-折叠结构转变为无规卷曲结构。通过聚类分析，发现C30在PFH 6寡聚体上有4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L1和L3层之间。疏水相互作用是C30与PHF 6寡聚体结合的驱动力。此外，L1P4_Y310、L1P5_Y310、L3P1_V309和L3P2_V309是C30与寡聚体结合的关键残基。L1P4_Y310和L1P5_Y310与C30形成的π-π相互作用以及C30与L3P3_Q307形成的氢键相互作用有利于C30与齐聚物的结合。充分了解2，4-噻唑烷二酮衍生物对PHF 6寡聚体的破坏机制以及结合位点的确定将有助于未来设计和发现新的AD抑制剂。
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.