A Solid State ~(13)C NMR, Crystallographic, and Quantum Chemical Investigation of Chemical Shifts and Hydrogen Bonding in Histidine Dipeptides

摘要

We report the first solid-state NMR, crystallographic, and quantum chemical investigation of the origins of the ~(13)C NMR chemical shifts of the imidazole group in histidine-containing dipeptides. The chemical shift ranges for C~γ and C~(δ_2) seen in eight crystalline dipeptides were very large (12.7-13.8 ppm); the shifts were highly correlated (R~2 = 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 ~(13)C 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 R~2 = 0.93) and N~(ε_2)…H…N (average R~2 = 0.98) hydrogen bond lengths. For C~(ε_1) the ~(13)C chemical shifts were also highly correlated with each of these properties (at the N~(ε_2) site), indicating the dominance of intermolecular interactions for C~(ε_1). These results open up the way to analyzing ~(13)C NMR chemical shifts, tautomer states (from C~(δ_2) C~(ε_1) shifts), and hydrogen bond properties (from C~(ε_1) shifts) of histidine residue in proteins and should be applicable to imidazole-containing drug molecules bound to proteins, as well.