We report the first solid-state NMR, crystallographic, and quantum chemical investigation of the origins of the 13C NMR chemical shifts of the imidazole group in histidine-containing dipeptides. The chemical shift ranges for Cγ and Cδ2 seen in eight crystalline dipeptides were very large (12.7-13.8 ppm); the shifts were highly correlated (R2 = 0.90) and were dominated by ring tautomer effects and intermolecular interactions. A similar correlation was found in proteins, but only for buried residues. The imidazole 13C NMR chemical shifts were predicted with an overall rms error of 1.6-1.9 ppm over a 26 ppm range, by using quantum chemical methods. Incorporation of hydrogen bond partner molecules was found to be essential in order to reproduce the chemical shifts seen experimentally. Using AIM (atoms in molecules) theory we found that essentially all interactions were of a closed shell nature and the hydrogen bond critical point properties were highly correlated with the N⋯H⋯O (average R2 = 0.93) and Nε2⋯H⋯N (average R 2 = 0.98) hydrogen bond lengths. For Cε1, the 13C chemical shifts were also highly correlated with each of these properties (at the Nε2 site), indicating the dominance of intermolecular interactions for Cε1. These results open up the way to analyzing 13C NMR chemical shifts, tautomer states (from Cδ2, Cε1 shifts), and hydrogen bond properties (from Cε1 shifts) of histidine residue in proteins and should be applicable to imidazole-containing drug molecules bound to proteins, as well.
ASJC Scopus subject areas
- Colloid and Surface Chemistry