New Hypothesis\non Enhancing β‑Sheet Formation\nduring the Tau Fragment Dimer Transition from a Flexible Monomer:\nInsights into Primary Nucleation Processes by Histidine Behaviors

Slight perturbations in pH can have significant effects\non the\nprimary nucleation processes of the tau protein. The behaviors of\nhistidine due to its pivotal role in modulating H-bonding network\ninteractions and electrostatic interactions have garnered considerable\nattention, as it can influence the structural characteristics and\naggregation properties. However, the nucleation mechanisms and related\nintermediates are still unclear. In the current study, we performed\nnine independent replica exchange molecular dynamics simulations to\ninvestigate dimer formation involving R3(εδ) in conjunction\nwith the R1, R2, and R4 monomers. Our findings substantiate that,\nin comparison to R1–R3(εδ) and R4–R3(εδ)\nsystems, the R2–R3(εδ) systems consistently manifest\nthe highest averaged β-sheet content, with the fundamental feature\nof R3(εδ) promoting R2 rearrangement. Our comprehensive\nanalysis reveals that high-β-sheet-rich systems exhibit a conserved\nthree/five β-strand structure. In these β-strand-rich\nsystems, one chain [R1/R2/R4 or R3(εδ)] with robust intrachain\nH-bonding interactions coordinates with another chain through interchain\nH-bonding interactions, contributing to the overall stability. Furthermore,\nwe discuss distinct histidine behaviors, including backbone/side chain\ninteractions and donor/acceptor roles. This study provides a comprehensive\nunderstanding of the aggregation propensities of soluble tau oligomers\nand sheds light on the primary nucleation mechanism. It contributes\nto a new perspective for understanding protein folding and misfolding.