Newly identified C-HMIDLINE HORIZONTAL ELLIPSISO hydrogen bond in histidine

New C delta-HMIDLINE HORIZONTAL ELLIPSISO histidine hydrogen bonding interactions in various proteins are identified by neutron diffraction and computationally characterized. Neutron diffraction data shows several H-bond motifs with the C delta-H moiety in histidine side chains, including interactions in beta-sheets and with coordinated waters, mostly with histidinium and tau-tautomers. In yellow protein, an active site histidine H-bonds via C delta-H to a main chain carbonyl while the C epsilon-H bond coordinates a water molecule. Although the H-bonding ability of C epsilon-H bonds in histidine have been previously identified, analysis of neutron diffraction structures reveals C epsilon-H H-bonds in notable active site interactions: for the proximal histidine in myoglobin; a zinc-bound histidine in human carbonic anhydrase II; within the Ser-Asp-His catalytic triad of the trypsin active site; and a histidine in the proton shuttle mechanism of RNase A, in addition to more general roles of coordinating water and forming H-bonds with carbonyl groups in beta-sheets within a number of proteins. Properties of these H-bonds were computationally investigated using 5-methylimidazole and 5-methylimidazolium as models for histidine and histidinium. The pi- and tau-tautomeric states of 5-methylimidazole were investigated, as both histidine tautomers are observed in the crystal structures. The newly characterized C epsilon-HMIDLINE HORIZONTAL ELLIPSISO and C delta-HMIDLINE HORIZONTAL ELLIPSISO model complexes with water and acetone meet the overwhelming majority of IUPAC H-bonding criteria. 5-Methylimidazolium forms complexes that are nearly twice as strong as the respective neutral tau-5-methylimidazole and pi-5-methylimidazole complexes. While the tau- and pi-tautomers form C epsilon-HMIDLINE HORIZONTAL ELLIPSISO complexes of similar strength, the tau-C delta-HMIDLINE HORIZONTAL ELLIPSISO interaction is approximately twice as strong as the pi-C delta-HMIDLINE HORIZONTAL ELLIPSISO interaction. Calculated charges on C-H (and N-H) hydrogens not participating in the H-bond are only slightly perturbed upon complex formation, implying that formation of one H-bond does not diminish the molecule's capacity for further H-bond formation at other sites in the imidazole ring. Overall, findings indicate that the C delta-HMIDLINE HORIZONTAL ELLIPSISO interaction may be important for beta-sheet stability, conformation, interactions with solvent, and mechanisms in the active site. Recognition of C-H bond polarity and hydrogen bonding ability in histidine may improve molecular modeling and provide further insight into the diverse roles of histidine in protein structure-function-dynamics.