Histidine behaviors effect on β-sheet-rich dimer formation of Tau R3 fragment: New insights on primary nucleation...

Slight perturbations in pH can significantly affect the primary nucleation processes of Tau protein. Histidine, due to its crucial role in modulating hydrogen bonding networks and electrostatic interactions, has garnered considerable attention. However, the precise nucleation mechanisms and the intermediates involved remain unclear. In the current study, we performed nine independent replica exchange molecular dynamics simulations to investigate dimer formation involving the dimer of the seeding R3(εδ) in conjunction with different R3 monomers. Our findings substantiate that, the R3(εε)-R3(εδ) system consistently manifests the highest averaged β-sheet content, with fundamental feature of R3(εδ) promoting R3 re-arrangement. Our comprehensive analysis reveals that high β-sheet-rich systems exhibit a conserved three/four β-strands structure. In these β-strand-rich systems, one chain (R3 or R3(εδ)) with robust intrachain H-bonding interactions coordinates with another chain through interchain H-bonding interactions, contributing to overall stability. Moreover, we explore the distinct behaviors of histidine, including its interactions within the mainchain and sidechain, as well as its roles as a donor and acceptor. This study provides insight into the R3-mediated aggregation propensity of soluble Tau oligomers and proposes a fragment-based model to elucidate the primary nucleation mechanism. It offers a new perspective on protein folding and misfolding.