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

ABSTRACT: Histidine state (protonated or δ or ε tautomer) has been considered the origin of abnormal misfolding and aggregation of β-amyloid (Aβ). Our previous studies reported that the δδδ isomer of Aβ (1-40) has a greater propensity for β-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 δδδ, εεε, and πππ (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 β-sheet formation is favored for the δδδ and πππ 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^-1, 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 Aβ (1-40) on amyloid misfolding and provides a connection between our previous simulations and experimental observations.

SUBMITTER: Nam Y

PROVIDER: S-EPMC7451942 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Infrared spectroscopy is playing an important role in the elucidation of amyloid fiber formation, but the coupling models that link spectra to structure are not well tested for parallel β-sheets. Using a synthetic macrocycle that enforces a two stranded parallel β-sheet conformation, we measured the lifetimes and frequency for six combinations of doubly (13)C═(18)O labeled amide I modes using 2D IR spectroscopy. The average vibrational lifetime of the isotope labeled residues was 550 fs. The frequencies of the labels ranged from 1585 to 1595 cm(-1), with the largest frequency shift occurring for in-register amino acids. The 2D IR spectra of the coupled isotope labels were calculated from molecular dynamics simulations of a series of macrocycle structures generated from replica exchange dynamics to fully sample the conformational distribution. The models used to simulate the spectra include through-space coupling, through-bond coupling, and local frequency shifts caused by environment electrostatics and hydrogen bonding. The calculated spectra predict the line widths and frequencies nearly quantitatively. Historically, the characteristic features of β-sheet infrared spectra have been attributed to through-space couplings such as transition dipole coupling. We find that frequency shifts of the local carbonyl groups due to nearest neighbor couplings and environmental factors are more important, while the through-space couplings dictate the spectral intensities. As a result, the characteristic absorption spectra empirically used for decades to assign parallel β-sheet secondary structure arises because of a redistribution of oscillator strength, but the through-space couplings do not themselves dramatically alter the frequency distribution of eigenstates much more than already exists in random coil structures. Moreover, solvent exposed residues have amide I bands with >20 cm(-1) line width. Narrower line widths indicate that the amide I backbone is solvent protected inside the macrocycle. This work provides calculated and experimentally verified couplings for parallel β-sheets that can be used in structure-based models to simulate and interpret the infrared spectra of β-sheet containing proteins and protein assemblies, such as amyloid fibers.

Dataset Information

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

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