Role of the English (H6R) Mutation on the Structural Properties of Aβ40 and Aβ42 Owing to the Histidine Tautomeric Effect

As an intrinsic origin cause, histidine behaviors play a critical role in protein misfolding processes. Generally, the English (H6R) mutation will disrupt H6 interactions. However, the structural properties of Aβ40 H6R and Aβ42 H6R under the complex influence of a histidine tautomeric effect and an H6R mutation remain unclear. Therefore, we performed a replica exchange molecular dynamics simulation to unveil such structural properties. Our result showed that the H6R substitute could promote the generation of β-sheet structures in comparison to the wild type. Three β-strand structure properties were observed in Aβ40 (rδδ), Aβ42 (rϵϵ), Aβ42 (rϵδ), and Aβ42 (rδδ) with β-sheet contents of 47.5%, 37.2%, 46.9%, and 38.6%, respectively, and the dominant conformational properties of Aβ40 (rδδ), Aβ42 (rϵϵ), Aβ42 (rϵδ), and Aβ42 (rδδ) had top conformational states of 86.0%, 73.2%, 67.0%, and 56.5%, respectively. Further analysis confirmed that R6 had different mechanisms for controlling the conformational features in Aβ40 H6R and Aβ42 H6R. In the Aβ40 systems, H14 H-bond networks played a critical role in controlling the structural properties. However, in the Aβ42 systems, R6 was more important because it was directly involved in the β-strand formation and maintained the β-sheet between the N-terminus and the central hydrophobic core region. Our current study helps to elucidate the histidine tautomeric behaviors in H6R mutations, which will present opportunities to understand the correlation between with/without H6 and the Aβ40/Aβ42 H6R misfolding mechanisms.