| Autor: |
Sun Y; School of Chemistry and Chemical Engineering, Institute of Molecular Science, Shanxi University, Taiyuan, Shanxi 030006, People's Republic of China., Shi Y; School of Chemistry and Chemical Engineering, Institute of Molecular Science, Shanxi University, Taiyuan, Shanxi 030006, People's Republic of China., Li J; School of Chemistry and Chemical Engineering, Institute of Molecular Science, Shanxi University, Taiyuan, Shanxi 030006, People's Republic of China., Qian A; Institute of Resources and Environment Engineering, Shanxi University, Taiyuan, Shanxi 030006, People's Republic of China., Shi H; School of Chemistry and Chemical Engineering, Institute of Molecular Science, Shanxi University, Taiyuan, Shanxi 030006, People's Republic of China. |
| Abstrakt: |
Slight perturbations in pH can have significant effects on the primary nucleation processes of the tau protein. The behaviors of histidine due to its pivotal role in modulating H-bonding network interactions and electrostatic interactions have garnered considerable attention, as it can influence the structural characteristics and aggregation properties. However, the nucleation mechanisms and related intermediates are still unclear. In the current study, we performed nine independent replica exchange molecular dynamics simulations to investigate dimer formation involving R3(εδ) in conjunction with the R1, R2, and R4 monomers. Our findings substantiate that, in comparison to R1-R3(εδ) and R4-R3(εδ) systems, the R2-R3(εδ) systems consistently manifest the highest averaged β-sheet content, with the fundamental feature of R3(εδ) promoting R2 rearrangement. Our comprehensive analysis reveals that high-β-sheet-rich systems exhibit a conserved three/five β-strand structure. In these β-strand-rich systems, one chain [R1/R2/R4 or R3(εδ)] with robust intrachain H-bonding interactions coordinates with another chain through interchain H-bonding interactions, contributing to the overall stability. Furthermore, we discuss distinct histidine behaviors, including backbone/side chain interactions and donor/acceptor roles. This study provides a comprehensive understanding of the aggregation propensities of soluble tau oligomers and sheds light on the primary nucleation mechanism. It contributes to a new perspective for understanding protein folding and misfolding. |
