Tautomeric Effect of Histidine on β-Sheet Formation of Amyloid Beta 1–40: 2D-IR Simulations

Abstract

Histidine state (protonated or d or ε tautomer) has been considered the origin of abnormal misfolding and aggregation of b-amyloid (Ab). Our previous studies reported that the ddd isomer of Ab (1-40) has a greater propensity for b-sheet conformation compared to other isomers. However, direct proof of the tautomeric effect has not been reported. In this context, we calculated histidine site-specific two-dimensional infrared spectroscopy of the ddd, εεε, and ppp (all protonated histidine) systems within the framework of classical molecular dynamics simulations aiming at connecting our previous results with the current experimental observations. Our results showed that b-sheet formation is favored for the ddd and ppp tautomers compared with the εεε tautomer, consistent with our previous studies. This result was further supported by contact map analyses and the strength of dipole coupling between the amide-I bonds of each residue. The two-dimensional infrared diagonal trace for each tautomer included three distinctive spectrally resolvable peaks near 1680, 1686, and 1693 cm À1 , as was also observed for histidine dipeptides. However, the peak positions at His6, His13, and His14 did not show a consensus trend with the histidine or protonation state but were instead affected by the presence of surrounding hydrogen bonds. Our study provides a deeper insight into the influence of tautomerism and protonation of histidine residues in Ab (1-40) on amyloid misfolding and provides a connection between our previous simulations and experimental observations.

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

“…The CHC//N-terminus and CHC//C-terminus were the interaction regions of the β-strand structures. Many reports are available on such three β-strand structures. , In contrast, in Aβ42 H6R, except Aβ42 (rδε), which is prone to a nondominant conformational feature, Aβ42 (rεε), Aβ42 (rεδ), and Aβ42 (rδδ) had dominant conformational properties with top conformational states of 73.2%, 67.0%, and 56.5%, respectively. Similarly, the CHC//N-terminus and CHC//C-terminus were the interaction regions.…”

Monitoring early-stage β-amyloid dimer aggregation by histidine site-specific two-dimensional infrared spectroscopy in a simulation study

“…28 In our earlier research, we revealed that Aβ40 monomers carrying the His6(δ)–His13(δ)–His14(δ) (the so-called δδδ isomeric form) and His6(π)–His13(π)–His14(π) isomer (πππ) leads to greater amounts of β-structure generation, as compared with the His6(ε)–His13(ε)–His14(ε) (εεε) tautomeric isomer. 29…”

Theoretical Insights into Mutation and Histidine Tautomerism Effects on Tau Proteins

“…21,22 Furthermore, we performed two-dimensional infrared (2D IR) analysis to characterize the H-bond and charge networks in a dipeptide model for different states of histidine tautomers. 23 On the basis of the theoretical studies, the histidine tautomerism hypothesis was proposed for protein misfolding. More relevant research is needed to verify and develop this hypothesis.…”

“…Some isomers of peptides under histidine tautomeric effect are more toxic relative to wild type. Because of the importance of oligomers in the misfolding of Aβ proteins, we investigated the structural properties of the Aβ homodimer and pentamer. , Furthermore, we performed two-dimensional infrared (2D IR) analysis to characterize the H-bond and charge networks in a dipeptide model for different states of histidine tautomers . On the basis of the theoretical studies, the histidine tautomerism hypothesis was proposed for protein misfolding.…”