Solid state 13C NMR, crystallographic, and quantum chemical investigation of chemical shifts and hydrogen bonding in histidine dipeptides

We report the first solid-state NMR, crystallographic, and quantum chemical investigation of the origins of the C-13 NMR chemical shifts of the imidazole group in histidine-containing dipeptides, The chemical shift ranges for C-gamma and C-delta 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 C-13 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 point properties were highly correlated with the N center dot center dot center dot H center dot center dot center dot O (average R-2 = 0.93) and N-delta 1 center dot center dot center dot H center dot center dot center dot N (average R-2 = 0.98) hydrogen bond lengths. For C-1, the C-13 Chemical shifts were also highly correlated with each these properties (at the N-epsilon 2 site), indicating the dominance of intermolecular interactions for C-epsilon 1. results open up the way to analyzing C-13 NMR chemical shifts, tautomer states (from C-delta 1 C-'(1) shifts), hydrogen bond properties (from C-epsilon 1, shifts) of histidine residue in proteins and should be applicable imidazole-containing drug molecules bound to proteins, as well.