N–H···N Hydrogen Bonds Involving Histidine Imidazole Nitrogen Atoms: A New Structural Role for Histidine Residues in Proteins

The amino acid histidine can play a significant role in the structure and function of proteins. Its various functions include enzyme catalysis, metal binding activity, and involvement in cation−π, π–π, salt-bridge, and other types of noncovalent interactions. Although histidine’s imidazole nitrogens (Nδ and Nε) are known to participate in hydrogen bond (HB) interactions as an acceptor or a donor, a systematic study of N–H···N HBs with the Nδ/Nε atom as the acceptor has not been conducted. In this study, we have examined two data sets of ultra-high-resolution (data set I) and very high-resolution (data set II) protein structures and identified 28 and 4017 examples of HBs of the N–H···Nδ/Nε type from both data sets involving histidine imidazole nitrogen as the acceptor. In nearly 70% of them, the main-chain N–H bond is the HB donor, and a majority of the examples are from the N–H group separated by two residues (N_i+2–H_i+2) from histidine. Quantum chemical calculations using model compounds were performed with imidazole and N-methylacetamide, and they assumed conformations from 19 examples from data set I with N–H···Nδ/Nε HBs. Basis set superposition error-corrected interaction energies varied from −5.0 to −6.78 kcal/mol. We also found that the imidazole nitrogen of 9% of histidine residues forming N–H···Nδ/Nε interactions in data set II participate in bifurcated HBs. Natural bond orbital analyses of model compounds indicate that the strength of each HB is mutually influenced by the other. Histidine residues involved in N_i+2–H_i+2···Nδ_i/Nε_i HBs are frequently observed in a specific N-terminal capping position giving rise to a novel helix-capping motif. Along with their predominant occurrence in loop segments, we propose a new structural role for histidines in protein structures.