Histidine Protonation Behaviors on Structural Properties and Aggregation Properties of Aβ(1–42) Mature Fibril: Approaching by Edge Effects

The histidine behavior plays a crucial role in the structural and aggregation properties of protein folding and misfolding. Understanding the histidine behavior at the edge of the protein structure is critical for finding ways to disrupt fibril elongation and growth, but this impact remains poorly understood. In the current study, we used molecular dynamics simulations to investigate the edge substitution effect of histidine protonation on the structural and aggregation properties. Our data showed that ΔG1contributed the most to binding affinity compared to ΔG2and ΔG3. The different protonation states at the edge chain significantly impacted the secondary structure properties of the edge chain. Specifically, we found that such protonation behavior significantly affected specific regions, particularly the N-terminus (G9-Q15) and C-terminus (K28-A30). Further analysis confirmed that H6, H13, and H14 were directly involved in H-bonding networks with the C1_H14//C2_H13 interchain interactions critical for maintaining the interchain stability. Furthermore, we confirmed that H6, H13, and H14 were directly involved in the loss of the carbon skeleton contact in the N-terminus. Our findings indicate that the edge condition is more susceptible to changes in structural properties than the middle condition. The current study is helpful for understanding the histidine behavior hypothesis in related misfolding diseases.