Interpretingthe Histidine-Containing Small Peptideson Tau Protein Tautomerism: A Theoretical Perspective

Exploring the nature of histidine residue tautomerization via a systematic conformational study is essential for understanding the pathology and toxicity of several neurodegenerative diseases, as well as for their diagnosis and treatment. Herein, density functional theory (DFT) calculations were used to determine the Tau protein’s histidine-containing dipeptide (Lys-His, His-Gln, and His-Val) and tripeptide (Lys-His-Gln and Lys-His-Val) isomeric conformations via intramolecular hydrogen bond interactions, with particular attention to the influence of N–H group isomeric forms on their properties. The calculated infrared (IR) spectroscopy of the N–H stretch region of each isomer and nuclear magnetic resonance (NMR) shielding of the imidazole ring carbon atoms (¹³C¹, ¹³C², and ¹³C³) were investigated. The results show that both the IR spectrum of the N–H group and the NMR shielding of ¹³C nuclei on the imidazole ring can be used to identify the histidine-containing dipeptide and tripeptide tautomeric isomers. Systematically analyzing the hydrogen bonding interactions, the atomic charge distribution, the potential energy distribution, and the HOMO–LUMO transitions of each isomer further verified the above conclusions. This study provides theoretical evidence for the conformation identification of the histidine-containing dipeptide and tripeptide isomers on Tau protein.