TY - JOUR
T1 - Molecular dynamics simulations reveal the disruption mechanism of a 2,4-thiazolidinedione derivative C30 against tau hexapeptide (PHF6) oligomer
AU - Liu, Hongli
AU - Zhong, Haiyang
AU - Liu, Huanxiang
AU - Yao, Xiaojun
N1 - Publisher Copyright:
© 2021 Wiley Periodicals LLC.
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
KW - 2,4-thiazolidinedione derivative
KW - MM-GBSA
KW - PHF6
KW - molecular dynamics simulation
KW - tau
UR - http://www.scopus.com/inward/record.url?scp=85113603577&partnerID=8YFLogxK
U2 - 10.1002/prot.26196
DO - 10.1002/prot.26196
M3 - Article
C2 - 34331342
AN - SCOPUS:85113603577
SN - 0887-3585
VL - 90
SP - 142
EP - 154
JO - Proteins: Structure, Function and Bioinformatics
JF - Proteins: Structure, Function and Bioinformatics
IS - 1
ER -